Dr Benjamin Bax
Darllenydd
Ysgol y Biowyddorau
- BaxB@caerdydd.ac.uk
- +44 29225 11070
- Y Prif Adeilad, Plas y Parc, Caerdydd, CF10 3AT
Trosolwyg
Rwy'n Ddarllenydd mewn Bioleg Strwythurol yn y Sefydliad Darganfod Meddyginiaethau ym Mhrifysgol Caerdydd. Nod y Sefydliad yw trosi dealltwriaeth o fecanweithiau clefydau yn ddulliau therapiwtig newydd ar gyfer cleifion sydd angen gwell opsiynau triniaeth. Gall gwybodaeth strwythurol am sut mae cyfansoddion yn rhwymo i'w proteinau targed helpu cemegwyr i ddylunio moleciwlau gwell a gall lywio strategaethau ar gyfer gwneud therapiwteg newydd.
Bûm yn gweithio i GlaxoSmithKline am ddeunaw mlynedd (1998-2016); cefnogi timau prosiect gyda data strwythurol, ar ystod o niwrowyddoniaeth, gwrth-ficrobaidd a thargedau eraill, gan gynnwys modulatyddion positif derbynyddion AMPA (Ward, Bax a Harries, 2010; DOI: 10.1111 / j.1476-5381.2010.00726.x)
Cefnogais y tîm a ddatblygodd y gepotidacin gwrthfiotig newydd (llwyddiannus yng ngham III) gyda data strwythurol (Bax, et al ., 2010 Nature, 466, tt. 935-940) ac rwyf wedi cyhoeddi llawer o strwythurau crisial o gyfadeiladau DNA-gyrase a chyfansoddion (gweler tabl 1 ar Tab Ymchwil - a chyhoeddiadau). Mae strwythurau yn awgrymu bod moleciwlau bach cydffurfiol hyblyg yn aml yn gwneud gwell atalyddion o'r targed cyffuriau cydymffurfiannol hyblyg hwn (cymhleth protein/DNA) na moleciwlau bach mwy anhyblyg.
Cyhoeddiad
2023
- Byl, J. A. W., Mueller, R., Bax, B., Basarab, G. S., Chibale, K. and Osheroff, N. 2023. A series of Spiropyrimidinetriones that enhances DNA cleavage mediated by Mycobacterium tuberculosis gyrase. ACS Infectious Diseases 9(3), pp. 706-715. (10.1021/acsinfecdis.3c00012)
- Morgan, H. et al. 2023. A 2.8 Å structure of zoliflodacin in a DNA cleavage complex with staphylococcus aureus DNA gyrase. International Journal of Molecular Sciences 24(2), article number: 1634. (10.3390/ijms24021634)
2022
- Bax, B. D., Sutormin, D., McDonald, N. Q., Burley, G. A. and Shelkovnikova, T. 2022. Oligonucleotide-recognizing topoisomerase inhibitors (OTIs): precision gene editors for neurodegenerative diseases. International Journal of Molecular Sciences 23(19), article number: 11541. (10.3390/ijms231911541)
- Elvers, K. T., Lipka-Lloyd, M., Trueman, R. C., Bax, B. D. and Mehellou, Y. 2022. Structures of the human SPAK and OSR1 conserved C-terminal (CCT) domains. ChemBioChem 23(1), article number: e202100441. (10.1002/cbic.202100441)
2020
- Fenn, G., Waller-Evans, H., Atack, J. R. and Bax, B. D. 2020. Crystallization and structure of ebselen bound to cysteine 141 of human inositol monophosphatase (IMPase). Acta Crystallographica Section F: Structural Biology Communications F76(10), pp. 469-476. (10.1107/S2053230X20011310)
- Koulouris, C. R., Bax, B. D., Atack, J. R. and Roe, S. M. 2020. Conformational flexibility within the small domain of human serine racemase. Acta Crystallographica Section F: Structural Biology Communications 76(2), pp. 65-73. (10.1107/S2053230X20001193)
2019
- Bax, B. D., Murshudov, G., Maxwell, A. and Germe, T. 2019. DNA Topoisomerase inhibitors: trapping a DNA-cleaving machine in motion. Journal of Molecular Biology 431(18), pp. 3427-3449. (10.1016/j.jmb.2019.07.008)
- Thalji, R. K. et al. 2019. Structure-guided design of antibacterials that allosterically inhibit DNA gyrase. Bioorganic and Medicinal Chemistry Letters 29(11), pp. 1407-1412. (10.1016/j.bmcl.2019.03.029)
- Gibson, E. G., Bax, B., Chan, P. F. and Osheroff, N. 2019. Mechanistic and structural basis for the actions of the antibacterial gepotidacin against Staphylococcus aureus gyrase. ACS Infectious Diseases 5(4), pp. 570-581. (10.1021/acsinfecdis.8b00315)
- Dehghani-Tafti, S., Levdikov, V., Antson, A. A., Bax, B. and Sanders, C. M. 2019. Structural and functional analysis of the nucleotide and DNA binding activities of the human PIF1 helicase. Nucleic Acids Research 47(6), pp. 3208-3222. (10.1093/nar/gkz028)
2018
- Gibson, E. G., Blower, T. R., Cacho, M., Bax, B., Berger, J. M. and Osheroff, N. 2018. Mechanism of action of mycobacterium tuberculosis gyrase Inhibitors: A novel class of gyrase poisons. ACS Infectious Diseases 4(8), pp. 1211. (10.1021/acsinfecdis.8b00035)
- Germe, T. et al. 2018. A new class of antibacterials, the imidazopyrazinones, reveal structural transitions involved in DNA gyrase poisoning and mechanisms of resistance. Nucleic Acids Research 46(8), pp. 4114-4128. (10.1093/nar/gky181)
- Lara, L. I., Fenner, S., Ratcliffe, S., Isidro-Llobet, A., Hann, M., Bax, B. and Osheroff, N. 2018. Coupling the core of the anticancer drug etoposide to an oligonucleotide induces topoisomerase II-mediated cleavage at specific DNA sequences. Nucleic Acids Research 46(5), pp. 2218-2233. (10.1093/nar/gky072)
2017
- Henley, Z. A. et al. 2017. From PIM1 to PI3Kδ via GSK3β: Target hopping through the kinome. ACS Medicinal Chemistry Letters 8(10), pp. 1093-1098. (10.1021/acsmedchemlett.7b00296)
- Chan, P. F. et al. 2017. Thiophene antibacterials that allosterically stabilize DNA-cleavage complexes with DNA gyrase. Proceedings of the National Academy of Sciences 114(22), pp. E4492-E4500. (10.1073/pnas.1700721114)
- Bax, B., Chung, C. and Edge, C. 2017. Getting the chemistry right: protonation, tautomers and the importance of H atoms in biological chemistry. Acta Crystallographica Section D Structural Biology 73(2), pp. 131-140. (10.1107/S2059798316020283)
2016
- Miles, T. J. et al. 2016. Novel tricyclics (e.g., GSK945237) as potent inhibitors of bacterial type IIA topoisomerases. Bioorganic and Medicinal Chemistry Letters 26(10), pp. 2464-2469. (10.1016/j.bmcl.2016.03.106)
2015
- Chan, P. F. et al. 2015. Structural basis of DNA gyrase inhibition by antibacterial QPT-1, anticancer drug etoposide and moxifloxacin. Nature Communications 6, article number: 10048. (10.1038/ncomms10048)
- Slade, D. J. et al. 2015. Protein arginine deiminase 2 binds calcium in an ordered fashion: implications for inhibitor design. ACS Chemical Biology 10(4), pp. 1043-1053. (10.1021/cb500933j)
- Lewis, H. D. et al. 2015. Inhibition of PAD4 activity is sufficient to disrupt mouse and human NET formation. Nature Chemical Biology 11(3), pp. 189-191. (10.1038/nchembio.1735)
- Srikannathasan, V. et al. 2015. Crystallization and initial crystallographic analysis of covalent DNA-cleavage complexes ofStaphyloccocus aureusDNA gyrase with QPT-1, moxifloxacin and etoposide. Acta Crystallographica Section F Structural Biology Communications 71(10), pp. 1242-1246. (10.1107/S2053230X15015290)
2014
- Li, D. et al. 2014. Crystallizing membrane proteins in the lipidic mesophase. Experience with human prostaglandin e2 synthase 1 and an evolving strategy. Crystal Growth and Design 14(4), pp. 2034-2047. (10.1021/cg500157x)
2013
- Agrawal, A. et al. 2013. Mycobacterium tuberculosisDNA gyrase ATPase domain structures suggest a dissociative mechanism that explains how ATP hydrolysis is coupled to domain motion. Biochemical Journal 456(2), pp. 263-273. (10.1042/BJ20130538)
- Chan, P. F., Huang, J., Bax, B. and Gwynn, M. N. 2013. Recent developments in inhibitors of bacterial type IIA topoisomerases. In: Gualerzi, C. O., Brandi, L. and Pon, C. L. eds. Antibiotics: Targets, Mechanisms and Resistance. Wiley, pp. 263., (10.1002/9783527659685.ch11)
- Miles, T. J. et al. 2013. Novel hydroxyl tricyclics (e.g., GSK966587) as potent inhibitors of bacterial type IIA topoisomerases. Bioorganic and Medicinal Chemistry Letters 23(19), pp. 5437-5441. (10.1016/j.bmcl.2013.07.013)
- Roué, M., Agrawal, A., Volker, C., Mossakowska, D., Mayer, C. and Bax, B. D. 2013. Purification, crystallization and preliminary X-ray crystallographic studies of the Mycobacterium tuberculosis DNA gyrase ATPase domain. Acta Crystallographica Section F F69(6), pp. 679-682. (10.1107/S1744309113012906)
2012
- Gentile, G. et al. 2012. 5-Aryl-4-carboxamide-1,3-oxazoles: Potent and selective GSK-3 inhibitors. Bioorganic and Medicinal Chemistry Letters 22(5), pp. 1989-1994. (10.1016/j.bmcl.2012.01.034)
2011
- Gentile, G. et al. 2011. Identification of 2-(4-pyridyl)thienopyridinones as GSK-3β inhibitors. Bioorganic and Medicinal Chemistry Letters 21(16), pp. 4823-4827. (10.1016/j.bmcl.2011.06.050)
- Ward, S. et al. 2011. Integration of lead optimization with crystallography for a membrane-bound ion channel target: discovery of a new class of AMPA receptor positive allosteric modulators. Journal of Medicinal Chemistry 54(1), pp. 78-94. (10.1021/jm100679e)
2010
- Wohlkonig, A. et al. 2010. Structural basis of quinolone inhibition of type IIA topoisomerases and target-mediated resistance. Nature Structural and Molecular Biology 17(99), pp. 1152-1153. (10.1038/nsmb.1892)
- Bax, B. D. et al. 2010. Type IIA topoisomerase inhibition by a new class of antibacterial agents. Nature 466(7309), pp. 935-940. (10.1038/nature09197)
- Ward, S. et al. 2010. Discovery of N-[(2S)-5-(6-Fluoro-3-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide, a novel clinical AMPA receptor positive modulator. Journal of Medicinal Chemistry 53(15), pp. 5801-5812. (10.1021/jm1005429)
- Ward, S., Bax, B. D. and Harries, M. 2010. Challenges for and current status of research into positive modulators of AMPA receptors. British Journal of Pharmacology 160(2), pp. 181-190. (10.1111/j.1476-5381.2010.00726.x)
2009
- Christopher, J. A. et al. 2009. 1-Aryl-3,4-dihydroisoquinoline inhibitors of JNK3. Bioorganic and Medicinal Chemistry Letters 19(8), pp. 2230-2234. (10.1016/j.bmcl.2009.02.098)
2004
- Smith, K. J. et al. 2004. The structure of MSK1 reveals a novel autoinhibitory conformation for a dual kinase protein. Structure 12(6), pp. 1067-1077. (10.1016/j.str.2004.02.040)
2001
- Bax, B. et al. 2001. The structure of phosphorylated GSK-3β complexed with a peptide, FRATtide, that inhibits β-catenin phosphorylation. Structure 9(12), pp. 1143-1152. (10.1016/S0969-2126(01)00679-7)
- Culbert, A. A., Brown, M. J., Frame, S., Hagen, T., Cross, D. A., Bax, B. and Reith, A. D. 2001. GSK‐3 inhibition by adenoviral FRAT1 overexpression is neuroprotective and induces Tau dephosphorylation and β‐catenin stabilisation without elevation of glycogen synthase activity. FEBS Letters 507(3), pp. 288-294. (10.1016/S0014-5793(01)02990-8)
- Tisi, D., Bax, B. and Loew, A. 2001. The three-dimensional structure of cytosolic bovine retinal creatine kinase. Acta Crystallographica Section D: Biological Crystallography 57(2), pp. 187-193. (10.1107/S0907444900015614)
2000
- Yarski, M. A., Bax, B., Hogue-Angeletti, R. A. and Bradshaw, R. A. 2000. Nerve growth factor α subunit: effect of site-directed mutations on catalytic activity and 7S NGF complex formation. Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology 1477(1-2), pp. 253-266. (10.1016/S0167-4838(99)00277-0)
1999
- Jones, D. H., Bax, B., Fensome, A. and Cockcroft, S. 1999. ADP ribosylation factor 1 mutants identify a phospholipase D effector region and reveal that phospholipase D participates in lysosomal secretion but is not sufficient for recruitment of coatomer I. Biochemical Journal 341(1), pp. 185-192. (10.1042/bj3410185)
1998
- Loew, A., Ho, Y., Blundell, T. and Bax, B. 1998. Phosducin induces a structural change in transducin ??. Structure 6(8), pp. 1007-1019. (10.1016/S0969-2126(98)00102-6)
- Loew, A. and Bax, B. 1998. Purification, crystallization and preliminary crystallographic analysis of bovine cytosolic brain-type creatine kinase. Acta Crystallographica Section D Biological Crystallography 54(5), pp. 989-990. (10.1107/S0907444998000985)
1997
- Bax, B., Blundell, T. L., Murray-Rust, J. and McDonald, N. Q. 1997. Structure of mouse 7S NGF: a complex of nerve growth factor with four binding proteins. Structure 5(10), pp. 1275-1285. (10.1016/S0969-2126(97)00280-3)
- Slingsby, C. et al. 1997. X-ray diffraction and structure of crystallins. Progress in Retinal and Eye Research 16(1), pp. 3-29. (10.1016/S1350-9462(96)00018-3)
- Tisi, D., Teahan, C., Greasley, S., Bax, B., Neu, M. and Jhoti, H. 1997. Common themes and surprising differences in small G-proteins. Biochemical Society Transactions 25(3), pp. 989-991. (10.1042/bst0250989)
1996
- Srinivasan, N., Bax, B., Blundell, T. and Parker, P. 1996. Structural aspects of the functional modules in human protein kinase-Cα deduced from comparative analyses. Proteins 26(2), pp. 217-235. (10.1002/(SICI)1097-0134(199610)26:2<217::AID-PROT11>3.0.CO;2-S)
- Zaitseva, I., Zaitsev, V., Card, G., Moshkov, K., Bax, B., Ralph, A. and Lindley, P. 1996. The X-ray structure of human serum ceruloplasmin at 3.1.Å: nature of the copper centres. JBIC Journal of Biological Inorganic Chemistry 1(1), pp. 15-23. (10.1007/s007750050018)
1995
- Bax, B. and Jhoti, H. 1995. Protein-protein interactions: putting the pieces together. Current Biology 5(10), pp. 1119-1121. (10.1016/S0960-9822(95)00226-0)
- Greasley, S. E. et al. 1995. The structure of rat ADP-ribosylation factor-1 (ARF-1) complexed to GDP determined from two different crystal forms. Nature Structural and Molecular Biology 2(9), pp. 797-806. (10.1038/nsb0995-797)
1994
- Nalini, V., Bax, B., Driessen, H., Moss, D., Lindley, P. and Slingsby, C. 1994. Close packing of an oligomeric eye lens β-crystallin induces loss of symmetry and ordering of sequence extensions. Journal of Molecular Biology 236(4), pp. 1250-1258. (10.1016/0022-2836(94)90025-6)
- Dhand, R. et al. 1994. PI 3-kinase: structural and functional analysis of intersubunit interactions.. EMBO Journal 13(3), pp. 511-521. (10.1002/j.1460-2075.1994.tb06289.x)
- Greasley, S., Jhoti, H., Fensome, A. C., Cockcroft, S., Thomas, G. M. and Bax, B. 1994. Crystallization and Preliminary X-ray Diffraction Studies on ADP-ribosylation Factor 1. Journal of Molecular Biology 244(5), pp. 651-653. (10.1006/jmbi.1994.1759)
1993
- Bax, B., Ferguson, G., Blaber, M., Sternberg, M. J. E. and Walls, P. H. 1993. Prediction of the three-dimensional structures of the nerve growth factor and epidermal growth factor binding proteins (kallikreins) and an hypothetical structure of the high molecular weight complex of epidermal growth factor with its binding protein. Protein Science 2(8), pp. 1229-1241. (10.1002/pro.5560020805)
1992
- Panayotou, G. et al. 1992. Interaction of the p85 subunit of PI 3-kinase and its N-terminal SH2 domain with a PDGF receptor phosphorylation site: structural features and analysis of conformational changes.. EMBO Journal 11(12), pp. 4261-4272. (10.1002/j.1460-2075.1992.tb05524.x)
1991
- Lapatto, R., Nalini, V., Bax, B., Driessen, H., Lindley, P., Blundell, T. and Slingsby, C. 1991. High resolution structure of an oligomeric eye lens β-crystallin: Loops, arches, linkers and interfaces in βB2 dimer compared to a monomeric γ-crystallin. Journal of Molecular Biology 222(4), pp. 1067-1083. (10.1016/0022-2836(91)90594-V)
- Driessen, H. P. C., Bax, B., Slingsby, C., Lindley, P. F., Mahadevan, D., Moss, D. S. and Tickle, I. J. 1991. Structure of Oligomeric β B2-crystallin: an application of the T2 translation function to an asymmetric unit containing two dimers. Acta Crystallographica Section B: Structural Science 47(6), pp. 987-997. (10.1107/S0108768191009163)
1990
- Bax, B. et al. 1990. X-ray analysis of βB2-crystallin and evolution of oligomeric lens proteins. Nature 347(6295), pp. 776-780. (10.1038/347776a0)
1989
- Bax, B. and Slingsby, C. 1989. Crystallization of a new form of the eye lens protein βB2-crystallin. Journal of Molecular Biology 208(4), pp. 715-717. (10.1016/0022-2836(89)90162-9)
1988
- Slingsby, C., Driessen, H., Mahadevan, D., Bax, B. and Blundell, T. 1988. Evolutionary and functional relationships between the basic and acidic β-crystallins. Experimental Eye Research 46(3), pp. 375-403. (10.1016/S0014-4835(88)80027-7)
1987
- Luchin, S. et al. 1987. Frog lens βA1-crystallin: the nucleotide sequence of the cloned cDNA and computer graphics modelling of the three-dimensional structure. Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology 916(2), pp. 163-171. (10.1016/0167-4838(87)90104-X)
Adrannau llyfrau
- Chan, P. F., Huang, J., Bax, B. and Gwynn, M. N. 2013. Recent developments in inhibitors of bacterial type IIA topoisomerases. In: Gualerzi, C. O., Brandi, L. and Pon, C. L. eds. Antibiotics: Targets, Mechanisms and Resistance. Wiley, pp. 263., (10.1002/9783527659685.ch11)
Erthyglau
- Byl, J. A. W., Mueller, R., Bax, B., Basarab, G. S., Chibale, K. and Osheroff, N. 2023. A series of Spiropyrimidinetriones that enhances DNA cleavage mediated by Mycobacterium tuberculosis gyrase. ACS Infectious Diseases 9(3), pp. 706-715. (10.1021/acsinfecdis.3c00012)
- Morgan, H. et al. 2023. A 2.8 Å structure of zoliflodacin in a DNA cleavage complex with staphylococcus aureus DNA gyrase. International Journal of Molecular Sciences 24(2), article number: 1634. (10.3390/ijms24021634)
- Bax, B. D., Sutormin, D., McDonald, N. Q., Burley, G. A. and Shelkovnikova, T. 2022. Oligonucleotide-recognizing topoisomerase inhibitors (OTIs): precision gene editors for neurodegenerative diseases. International Journal of Molecular Sciences 23(19), article number: 11541. (10.3390/ijms231911541)
- Elvers, K. T., Lipka-Lloyd, M., Trueman, R. C., Bax, B. D. and Mehellou, Y. 2022. Structures of the human SPAK and OSR1 conserved C-terminal (CCT) domains. ChemBioChem 23(1), article number: e202100441. (10.1002/cbic.202100441)
- Fenn, G., Waller-Evans, H., Atack, J. R. and Bax, B. D. 2020. Crystallization and structure of ebselen bound to cysteine 141 of human inositol monophosphatase (IMPase). Acta Crystallographica Section F: Structural Biology Communications F76(10), pp. 469-476. (10.1107/S2053230X20011310)
- Koulouris, C. R., Bax, B. D., Atack, J. R. and Roe, S. M. 2020. Conformational flexibility within the small domain of human serine racemase. Acta Crystallographica Section F: Structural Biology Communications 76(2), pp. 65-73. (10.1107/S2053230X20001193)
- Bax, B. D., Murshudov, G., Maxwell, A. and Germe, T. 2019. DNA Topoisomerase inhibitors: trapping a DNA-cleaving machine in motion. Journal of Molecular Biology 431(18), pp. 3427-3449. (10.1016/j.jmb.2019.07.008)
- Thalji, R. K. et al. 2019. Structure-guided design of antibacterials that allosterically inhibit DNA gyrase. Bioorganic and Medicinal Chemistry Letters 29(11), pp. 1407-1412. (10.1016/j.bmcl.2019.03.029)
- Gibson, E. G., Bax, B., Chan, P. F. and Osheroff, N. 2019. Mechanistic and structural basis for the actions of the antibacterial gepotidacin against Staphylococcus aureus gyrase. ACS Infectious Diseases 5(4), pp. 570-581. (10.1021/acsinfecdis.8b00315)
- Dehghani-Tafti, S., Levdikov, V., Antson, A. A., Bax, B. and Sanders, C. M. 2019. Structural and functional analysis of the nucleotide and DNA binding activities of the human PIF1 helicase. Nucleic Acids Research 47(6), pp. 3208-3222. (10.1093/nar/gkz028)
- Gibson, E. G., Blower, T. R., Cacho, M., Bax, B., Berger, J. M. and Osheroff, N. 2018. Mechanism of action of mycobacterium tuberculosis gyrase Inhibitors: A novel class of gyrase poisons. ACS Infectious Diseases 4(8), pp. 1211. (10.1021/acsinfecdis.8b00035)
- Germe, T. et al. 2018. A new class of antibacterials, the imidazopyrazinones, reveal structural transitions involved in DNA gyrase poisoning and mechanisms of resistance. Nucleic Acids Research 46(8), pp. 4114-4128. (10.1093/nar/gky181)
- Lara, L. I., Fenner, S., Ratcliffe, S., Isidro-Llobet, A., Hann, M., Bax, B. and Osheroff, N. 2018. Coupling the core of the anticancer drug etoposide to an oligonucleotide induces topoisomerase II-mediated cleavage at specific DNA sequences. Nucleic Acids Research 46(5), pp. 2218-2233. (10.1093/nar/gky072)
- Henley, Z. A. et al. 2017. From PIM1 to PI3Kδ via GSK3β: Target hopping through the kinome. ACS Medicinal Chemistry Letters 8(10), pp. 1093-1098. (10.1021/acsmedchemlett.7b00296)
- Chan, P. F. et al. 2017. Thiophene antibacterials that allosterically stabilize DNA-cleavage complexes with DNA gyrase. Proceedings of the National Academy of Sciences 114(22), pp. E4492-E4500. (10.1073/pnas.1700721114)
- Bax, B., Chung, C. and Edge, C. 2017. Getting the chemistry right: protonation, tautomers and the importance of H atoms in biological chemistry. Acta Crystallographica Section D Structural Biology 73(2), pp. 131-140. (10.1107/S2059798316020283)
- Miles, T. J. et al. 2016. Novel tricyclics (e.g., GSK945237) as potent inhibitors of bacterial type IIA topoisomerases. Bioorganic and Medicinal Chemistry Letters 26(10), pp. 2464-2469. (10.1016/j.bmcl.2016.03.106)
- Chan, P. F. et al. 2015. Structural basis of DNA gyrase inhibition by antibacterial QPT-1, anticancer drug etoposide and moxifloxacin. Nature Communications 6, article number: 10048. (10.1038/ncomms10048)
- Slade, D. J. et al. 2015. Protein arginine deiminase 2 binds calcium in an ordered fashion: implications for inhibitor design. ACS Chemical Biology 10(4), pp. 1043-1053. (10.1021/cb500933j)
- Lewis, H. D. et al. 2015. Inhibition of PAD4 activity is sufficient to disrupt mouse and human NET formation. Nature Chemical Biology 11(3), pp. 189-191. (10.1038/nchembio.1735)
- Srikannathasan, V. et al. 2015. Crystallization and initial crystallographic analysis of covalent DNA-cleavage complexes ofStaphyloccocus aureusDNA gyrase with QPT-1, moxifloxacin and etoposide. Acta Crystallographica Section F Structural Biology Communications 71(10), pp. 1242-1246. (10.1107/S2053230X15015290)
- Li, D. et al. 2014. Crystallizing membrane proteins in the lipidic mesophase. Experience with human prostaglandin e2 synthase 1 and an evolving strategy. Crystal Growth and Design 14(4), pp. 2034-2047. (10.1021/cg500157x)
- Agrawal, A. et al. 2013. Mycobacterium tuberculosisDNA gyrase ATPase domain structures suggest a dissociative mechanism that explains how ATP hydrolysis is coupled to domain motion. Biochemical Journal 456(2), pp. 263-273. (10.1042/BJ20130538)
- Miles, T. J. et al. 2013. Novel hydroxyl tricyclics (e.g., GSK966587) as potent inhibitors of bacterial type IIA topoisomerases. Bioorganic and Medicinal Chemistry Letters 23(19), pp. 5437-5441. (10.1016/j.bmcl.2013.07.013)
- Roué, M., Agrawal, A., Volker, C., Mossakowska, D., Mayer, C. and Bax, B. D. 2013. Purification, crystallization and preliminary X-ray crystallographic studies of the Mycobacterium tuberculosis DNA gyrase ATPase domain. Acta Crystallographica Section F F69(6), pp. 679-682. (10.1107/S1744309113012906)
- Gentile, G. et al. 2012. 5-Aryl-4-carboxamide-1,3-oxazoles: Potent and selective GSK-3 inhibitors. Bioorganic and Medicinal Chemistry Letters 22(5), pp. 1989-1994. (10.1016/j.bmcl.2012.01.034)
- Gentile, G. et al. 2011. Identification of 2-(4-pyridyl)thienopyridinones as GSK-3β inhibitors. Bioorganic and Medicinal Chemistry Letters 21(16), pp. 4823-4827. (10.1016/j.bmcl.2011.06.050)
- Ward, S. et al. 2011. Integration of lead optimization with crystallography for a membrane-bound ion channel target: discovery of a new class of AMPA receptor positive allosteric modulators. Journal of Medicinal Chemistry 54(1), pp. 78-94. (10.1021/jm100679e)
- Wohlkonig, A. et al. 2010. Structural basis of quinolone inhibition of type IIA topoisomerases and target-mediated resistance. Nature Structural and Molecular Biology 17(99), pp. 1152-1153. (10.1038/nsmb.1892)
- Bax, B. D. et al. 2010. Type IIA topoisomerase inhibition by a new class of antibacterial agents. Nature 466(7309), pp. 935-940. (10.1038/nature09197)
- Ward, S. et al. 2010. Discovery of N-[(2S)-5-(6-Fluoro-3-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide, a novel clinical AMPA receptor positive modulator. Journal of Medicinal Chemistry 53(15), pp. 5801-5812. (10.1021/jm1005429)
- Ward, S., Bax, B. D. and Harries, M. 2010. Challenges for and current status of research into positive modulators of AMPA receptors. British Journal of Pharmacology 160(2), pp. 181-190. (10.1111/j.1476-5381.2010.00726.x)
- Christopher, J. A. et al. 2009. 1-Aryl-3,4-dihydroisoquinoline inhibitors of JNK3. Bioorganic and Medicinal Chemistry Letters 19(8), pp. 2230-2234. (10.1016/j.bmcl.2009.02.098)
- Smith, K. J. et al. 2004. The structure of MSK1 reveals a novel autoinhibitory conformation for a dual kinase protein. Structure 12(6), pp. 1067-1077. (10.1016/j.str.2004.02.040)
- Bax, B. et al. 2001. The structure of phosphorylated GSK-3β complexed with a peptide, FRATtide, that inhibits β-catenin phosphorylation. Structure 9(12), pp. 1143-1152. (10.1016/S0969-2126(01)00679-7)
- Culbert, A. A., Brown, M. J., Frame, S., Hagen, T., Cross, D. A., Bax, B. and Reith, A. D. 2001. GSK‐3 inhibition by adenoviral FRAT1 overexpression is neuroprotective and induces Tau dephosphorylation and β‐catenin stabilisation without elevation of glycogen synthase activity. FEBS Letters 507(3), pp. 288-294. (10.1016/S0014-5793(01)02990-8)
- Tisi, D., Bax, B. and Loew, A. 2001. The three-dimensional structure of cytosolic bovine retinal creatine kinase. Acta Crystallographica Section D: Biological Crystallography 57(2), pp. 187-193. (10.1107/S0907444900015614)
- Yarski, M. A., Bax, B., Hogue-Angeletti, R. A. and Bradshaw, R. A. 2000. Nerve growth factor α subunit: effect of site-directed mutations on catalytic activity and 7S NGF complex formation. Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology 1477(1-2), pp. 253-266. (10.1016/S0167-4838(99)00277-0)
- Jones, D. H., Bax, B., Fensome, A. and Cockcroft, S. 1999. ADP ribosylation factor 1 mutants identify a phospholipase D effector region and reveal that phospholipase D participates in lysosomal secretion but is not sufficient for recruitment of coatomer I. Biochemical Journal 341(1), pp. 185-192. (10.1042/bj3410185)
- Loew, A., Ho, Y., Blundell, T. and Bax, B. 1998. Phosducin induces a structural change in transducin ??. Structure 6(8), pp. 1007-1019. (10.1016/S0969-2126(98)00102-6)
- Loew, A. and Bax, B. 1998. Purification, crystallization and preliminary crystallographic analysis of bovine cytosolic brain-type creatine kinase. Acta Crystallographica Section D Biological Crystallography 54(5), pp. 989-990. (10.1107/S0907444998000985)
- Bax, B., Blundell, T. L., Murray-Rust, J. and McDonald, N. Q. 1997. Structure of mouse 7S NGF: a complex of nerve growth factor with four binding proteins. Structure 5(10), pp. 1275-1285. (10.1016/S0969-2126(97)00280-3)
- Slingsby, C. et al. 1997. X-ray diffraction and structure of crystallins. Progress in Retinal and Eye Research 16(1), pp. 3-29. (10.1016/S1350-9462(96)00018-3)
- Tisi, D., Teahan, C., Greasley, S., Bax, B., Neu, M. and Jhoti, H. 1997. Common themes and surprising differences in small G-proteins. Biochemical Society Transactions 25(3), pp. 989-991. (10.1042/bst0250989)
- Srinivasan, N., Bax, B., Blundell, T. and Parker, P. 1996. Structural aspects of the functional modules in human protein kinase-Cα deduced from comparative analyses. Proteins 26(2), pp. 217-235. (10.1002/(SICI)1097-0134(199610)26:2<217::AID-PROT11>3.0.CO;2-S)
- Zaitseva, I., Zaitsev, V., Card, G., Moshkov, K., Bax, B., Ralph, A. and Lindley, P. 1996. The X-ray structure of human serum ceruloplasmin at 3.1.Å: nature of the copper centres. JBIC Journal of Biological Inorganic Chemistry 1(1), pp. 15-23. (10.1007/s007750050018)
- Bax, B. and Jhoti, H. 1995. Protein-protein interactions: putting the pieces together. Current Biology 5(10), pp. 1119-1121. (10.1016/S0960-9822(95)00226-0)
- Greasley, S. E. et al. 1995. The structure of rat ADP-ribosylation factor-1 (ARF-1) complexed to GDP determined from two different crystal forms. Nature Structural and Molecular Biology 2(9), pp. 797-806. (10.1038/nsb0995-797)
- Nalini, V., Bax, B., Driessen, H., Moss, D., Lindley, P. and Slingsby, C. 1994. Close packing of an oligomeric eye lens β-crystallin induces loss of symmetry and ordering of sequence extensions. Journal of Molecular Biology 236(4), pp. 1250-1258. (10.1016/0022-2836(94)90025-6)
- Dhand, R. et al. 1994. PI 3-kinase: structural and functional analysis of intersubunit interactions.. EMBO Journal 13(3), pp. 511-521. (10.1002/j.1460-2075.1994.tb06289.x)
- Greasley, S., Jhoti, H., Fensome, A. C., Cockcroft, S., Thomas, G. M. and Bax, B. 1994. Crystallization and Preliminary X-ray Diffraction Studies on ADP-ribosylation Factor 1. Journal of Molecular Biology 244(5), pp. 651-653. (10.1006/jmbi.1994.1759)
- Bax, B., Ferguson, G., Blaber, M., Sternberg, M. J. E. and Walls, P. H. 1993. Prediction of the three-dimensional structures of the nerve growth factor and epidermal growth factor binding proteins (kallikreins) and an hypothetical structure of the high molecular weight complex of epidermal growth factor with its binding protein. Protein Science 2(8), pp. 1229-1241. (10.1002/pro.5560020805)
- Panayotou, G. et al. 1992. Interaction of the p85 subunit of PI 3-kinase and its N-terminal SH2 domain with a PDGF receptor phosphorylation site: structural features and analysis of conformational changes.. EMBO Journal 11(12), pp. 4261-4272. (10.1002/j.1460-2075.1992.tb05524.x)
- Lapatto, R., Nalini, V., Bax, B., Driessen, H., Lindley, P., Blundell, T. and Slingsby, C. 1991. High resolution structure of an oligomeric eye lens β-crystallin: Loops, arches, linkers and interfaces in βB2 dimer compared to a monomeric γ-crystallin. Journal of Molecular Biology 222(4), pp. 1067-1083. (10.1016/0022-2836(91)90594-V)
- Driessen, H. P. C., Bax, B., Slingsby, C., Lindley, P. F., Mahadevan, D., Moss, D. S. and Tickle, I. J. 1991. Structure of Oligomeric β B2-crystallin: an application of the T2 translation function to an asymmetric unit containing two dimers. Acta Crystallographica Section B: Structural Science 47(6), pp. 987-997. (10.1107/S0108768191009163)
- Bax, B. et al. 1990. X-ray analysis of βB2-crystallin and evolution of oligomeric lens proteins. Nature 347(6295), pp. 776-780. (10.1038/347776a0)
- Bax, B. and Slingsby, C. 1989. Crystallization of a new form of the eye lens protein βB2-crystallin. Journal of Molecular Biology 208(4), pp. 715-717. (10.1016/0022-2836(89)90162-9)
- Slingsby, C., Driessen, H., Mahadevan, D., Bax, B. and Blundell, T. 1988. Evolutionary and functional relationships between the basic and acidic β-crystallins. Experimental Eye Research 46(3), pp. 375-403. (10.1016/S0014-4835(88)80027-7)
- Luchin, S. et al. 1987. Frog lens βA1-crystallin: the nucleotide sequence of the cloned cDNA and computer graphics modelling of the three-dimensional structure. Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology 916(2), pp. 163-171. (10.1016/0167-4838(87)90104-X)
Ymchwil
Research interests
I am a structural biologist/crystallographer. The main focus of my research is to try to understand how compounds (small molecules) interact with and moderate the activities of proteins. The aim of my research is to help support chemists by providing structures to assist in structure guided drug design (including identifying happy and unhappy waters).
Current major areas of research interest include:
- Structure-guided drug design with a focus on diseases of the central nervous system
- Inhibitors of bacterial type IIA topoisomerases (fluoroquinolones, twofold axis pockets-NBTIs etc.)
1. Structure-guided drug design with a focus on diseases of the central nervous system
Interests include AMPA receptors (10.1021/jm100679e), NMDA receptors and other targets.
2. Inhibitors of bacterial type IIA topoisomerases
Type IIA topoisomerases are essential enzymes that regulate DNA topology by creating a temporary four base-pair staggered double stranded DNA break. Compounds which stabilize DNA-cleavage complexes with bacterial type IIA topoisomerases include the highly successful fluoroquinolone class of drugs as well as two novel compounds in late stage clinical development, zoliflodacin and gepotidacin (a new class of antibiotic which GlaxoSmithKline (GSK) have in Phase III clinical trials for uncomplicated urinary tract infection and urogenital gonorrhoea).
Structures I determined, while working for GSK, included the first quinolone structure showing the important 'water-metal-ion bridge' (Wohlkonig et al., 2010; DOI: 10.1038/nsmb.1892). I also solved the first X-ray crystal structures of DNA complexes showing the binding modes of NBTIs such as gepotidacin (Bax et al.,2010; Gibson et al., 2019) and QPT-1 derivatives such as zoliflodacin (Chan et al., 2015). Because several S. aureus DNA gyrase complexes with DNA (Bax et al., 2019) have static disorder around the twofold axis of the ‘dimer’ – biological coordinates of ‘single complexes’ are available below – in table 1. See publications under reference tab for more details.
Note - these S.aureus DNA gyrase crystal structures include structures with clear views of the TOPRIM domain metal-ion binding sites – and suggest a single moving mechanism for DNA-cleavage. A 2.98Å yeast structure (pdb code: 3L4K) complicated by static disorder around a crystallographic twofold that was originally refined with two metals at each active site has been re-refined to be consistent with unambigous high resolution structures and coordinates for this yeast rerefined structure are available below in table 2.
TABLE 1 Coordinates of biological complexes of S.aureus DNA gyrase GyrBA fusion truncate with DNA and compounds.
Co-ordinates for biological complexes are available (click to upload) in the columns labelled ‘Coordinates for first (or second) complex in asymmetric unit’. Note the numbering scheme used is different from PDB numbering. If the complex has twofold disorder around the axis of the complex two complexes are available, representing the two orientations of the biological complex observed in the crystal structure. *Note most of the DNA complexes listed have one or two complexes in the asymmetric unit; but in the two apo structures (2xco and 2xcq, the GyrBA dimer sits on a crystallographic twofold and there is half a dimer in the asymmetric unit).
The S.aureus gyrase DNA complexes are all approx C2 symmetric and compounds have been observed in four distinct pockets: 1 (and 1'), 2D (on the twofold axis in the DNA), 2A (on the twofold axis between the two GyrA subunits), 3 (and 3').
no | PDB code + resolution | Inhibitor | Crystal coords. (BA-x numb.), Space-group [cell (a,b,c Å, and a,b,g °) ] | Coordinates for first complex in asym. unit* | Coordinates for second complex in asym. unit* | ||||||
1 | 1’ | 2D | 2A | 3 | 3’ | ||||||
1 | 2xcq 2.98 | none | - | - | - | - | - | - | P6122, 90,90,416 90,90,120 | ||
2 | 2xco 3.1 | none | - | - | - | - | - | - | P6122, 90,90,411 90,90,120 | ||
3 | 6fqv 2.6 | none | - | - | - | - | - | - | P21, 93,125,155 90,96,90 | ||
4 | 5cdr 2.65 | none | - | - | - | - | - | - | P61, 93,93,411 90,90,120 | ||
5 | 5iwi 1.98 | ‘237 | - | - | X | X | - | - | P61, 93,93,411 90,90,120 | ||
6 | 2xcs 2.1Å | ‘423 | - | - | X | X | - | - | P61, 93,93,413 90,90,120 | ||
7 | 6qtk 2.31Å | gepo' | - | - | X | X | - | - | P61, 93,93,409 90,90,120 | ||
8 | 6qtp 2.37Å | gepo' | - | - | X | X | - | - | P21, 86,124,94 90,117,90 | 6qtp-c2.pdb | |
9 | 5iwm 2.5Å | ‘237 | - | - | X | X | - | - | P61, 94,94,413 90,90,120 | ||
10 | 4bul 2.6Å | ‘587 | - | - | X | X | - | - | P61, 94,94,416 90,90,120 | ||
11 | 2xcr 3.5Å | ‘423 | - | - | X | X | - | - | P212121 113,165,308 90,90,90 | ||
12 | 5npp 2.22Å | ‘237 + Thp2 | - | - | X | X | X | X | P61, 93,93,410 90,90,120 | ||
13 | 5npk 1.98Å | Thp1 | - | - | - | - | X | X | P21, 89,121,169 90,90.1,90 | ||
14 | 6qx1 2.65Å | Benzois’3 | - | - | - | - | X | X | P61, 93,93,409 90,90,120 | ||
15 | 6qx2 3.4 | Benzois’3 | - | - | - | - | X | X | P21, 188, 410,94 90,120.2,90 | Six complexes in asym. unit. Poor resolution | |
16 | 5cdp 2.45Å | Etop. | X | - | - | - | - | - | P61, 93,93,411 90,90,120 | ||
17 | 5cdm 2.5Å | QPT-1 | X | X | - | - | - | - | P61, 94,94,412 90,90,120 | ||
18 | 5cdn 2.8Å | Etop. | X | X | - | - | - | - | P21, 90, 170, 125, 90, 102, 90 | ||
19 | 5cdq 2.95Å | Moxi. | X | X | - | - | - | - | P21, 88, 171,126, 90, 103, 90 | ||
20 | 6fqm 3.06Å | IPY-t1 | X | X | - | - | - | - | P21 88, 172, 125, 90, 103, 90 | ||
21 | 6fqS 3.11Å | IPY-t3 | X | X | - | - | - | - | P61, 94,94,420 90,90,120 | ||
22 | 5cdo 3.15Å | QPT-1 | X | X | - | - | - | - | P21, 91,170, 125, 90, 103, 90 | ||
23 | 2xct 3.35 | Cipro. | X | X | - | - | - | - | P21, 89,123,170 90,90.3,90 90 |
Footnote: ‘237 = GSK945237; ‘423 = GSK299423; gepo = geoptidacin; ‘587 = GSK966587; Thp2 = thiophene 2; Thp1 = thiophene 1; Benzois’3 = benzoisoxazole3; Etop. = etoposide; QPT-1 = QPT-1; moxi. = moxifloxacin; IPY-t1 = imidazopyrazinone-tricyclic 1; ; IPY-t3 = imidazopyrazinone-tricyclic 3; cipro = ciprofloxacin.
Table 2 Coordinates of biological complexes for the deposited and re-refined crystal structures of 3L4K
Because 3L4K sits on a crystallographic twofold axis, the observed 2.98Å electron density is effectively a convolution of two structures superposed, related by the crystallographic twofold axis. This makes refinement and interpretation of the electron density more challenging, and more ambiguous than would be the case for a 2.98Å X-ray crystal structure not suffering from such static disorder. Below are presented coordinates from the two interpretations of the data: 3lk4.pdb and the derived complexes, 3l4k-c1a.pdb and 3l4k-c1b.pdb are the originally published interpretation (Schmidt et al., 2010), while RR-3l4k.pdb and RR-3l4k-c1a.pdb and RR-3l4k-c1b.pdb are from the re-refinement coordinates (see Bax et al., 2019 for details).
PDB file | Active site 1 | Active site 2 | ||||||
---|---|---|---|---|---|---|---|---|
Metal site occupancies | WHD Tyr 782 | Metal site occupancies | WHD Tyr 782' | Crystallographic coordinates | Coordinates for biological complex | |||
A | B | A | B | |||||
Original 3L4K | 1.0 | 1.0 | Tyr | 1.0 | 1.0 | Tyr | ||
Re-refined RR-3L4K | 0.5 | 0.5 | Tyr | 0.5 | 0.5 | Tyr |
Bywgraffiad
Mae gen i BSc mewn Ffiseg a Chemeg o Brifysgol Nottingham a PhD mewn Protein Crystallography o'r adran crisialograffi yng Ngholeg Birkbeck, Prifysgol Llundain. Mae gen i angerdd am ddefnyddio dylunio cyffuriau strwythur-dywysedig i wneud meddyginiaethau newydd i wella iechyd pobl; a phrofiad sylweddol fel biolegydd strwythurol diwydiannol (yn gweithio i GlaxoSmithKline (GSK) o 1998-2016).
Roedd gen i dri goruchwyliwr rhagorol ar gyfer fy PhD, Tom Blundell, Peter Lindley a Christine Slingsby, a'r strwythur a gafwyd, o betaB2-crystallin, oedd y strwythur 'cyfnewid parth' cyntaf (Bax et al., 1990 - gweler tab Cyhoeddiadau am fanylion). Cyn symud i ddiwydiant yn 1998 gweithiais ar astudiaethau strwythurol ar nifer o broteinau gan gynnwys: ceruloplasmin (Zaitseva et al., 1996), PI 3-kinase (Panyotou et al., 1992; Dhand et al., 1994), protein kinase C (Srinivassan et al. 1996), 7S NGF (Bax et al., 1997), y ARF G-protein bach (Greasely et al., 1995) a chymhleth o phosducin gyda'r beta/gamma is-unedau o'r transducin protein G heterotrimerig (Loew et al., 1998).
Ymunais â SmithKlineBeecham (GlaxoSmithKline yn ddiweddarach) ym 1998 i weithio fel crisialograffydd protein mewn grŵp bioleg strwythurol newydd. Roedd strwythurau kinase protein wedi'u datrys yn cynnwys GSK-3beta (Bax et al., 2001; Christopher et al., 2009; Gentile et al., 2011, 2012; Henley et al., 2017). Helpodd strwythurau crisial modulatyddion positif derbynnydd AMPA ymlaen cemeg ar y targed niwrowyddoniaeth heriol hwn (Ward et al., 2010 a, b; Ward et al., 2011). Maes astudio mawr oedd gwrthfiotigau newydd (a chyffuriau gwrth-ganser) gan dargedu topoisomerases math II bacteriol (Bax et al., 2010, Chan et al., 2017, 2015, 2014, Miles et al., 2016, 2013, Srikannathasan et al., 2015, Agrawal et al., 2013, Wohlkonig et al., 2010; Germe et al., 2018; Bax et al., 2019). Penderfynodd strwythurau NBTI mewn cyfadeiladau â gyrase DNA a DNA helpu'r tîm i ddatblygu gepotidacin (Gibson et al., 2019); Gepotidacin yw'r aelod cyntaf o'r dosbarth NBTI o wrthfiotig i gwblhau treial clinigol cam III yn llwyddiannus.
Yn GSK cyd-gadeiriodd y grŵp meddalwedd bioleg strwythurol a hi oedd cynrychiolydd diwydiannol pwyllgor gwaith CCP4 (mae CCP4 yn gonsortiwm sy'n datblygu meddalwedd crisialograffig). Arweiniodd sgwrs o benwythnos astudio CCP4 2016 at bapur o'r enw: 'Getting the chemistry right: protonation, tautomers and the importance of H atoms in biological chemistry'.
Ymunais â'r Sefydliad Darganfod Meddyginiaethau yng Nghaerdydd yn 2018.