Dr Benjamin Bax
(he/him)
Reader
School of Biosciences
- BaxB@cardiff.ac.uk
- +44 29225 11070
- Main Building, Park Place, Cardiff, CF10 3AT
Overview
I am a Reader in Structural Biology in the Medicines Discovery Institute at Cardiff University. The goal of the Institute is to translate understanding of disease mechanisms into novel therapeutic approaches for patients in need of improved treatment options. Structural information about how compounds bind to their target proteins can help chemists design better molecules and can inform strategies for making novel therapeutics.
I worked for GlaxoSmithKline for eighteen years (1998-2016); supporting project teams with structural data, on a range of neuroscience, anti-microbial and other targets, including AMPA receptor positive modulators (Ward, Bax and Harries, 2010; DOI: 10.1111/j.1476-5381.2010.00726.x)
I supported the team who developed the new antibiotic gepotidacin (successful in phase III) with structural data (Bax, et al., 2010 Nature, 466, pp. 935-940) and have published many crystal structures of DNA-complexes of DNA-gyrase and compounds (see table 1 on Research tab - and publications). Structures suggest that for DNA gyrase conformationally flexible small molecules often make better inhibitors of this conformationally flexible drug target (protein/DNA complex) than more rigid small molecules.
Publication
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)
Articles
- 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)
Book sections
- 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)
Research
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, NBTIs, spiropyrimidinetriones etc.).
- OTIs. Oligonucleotide-recognizing topoisomerase inhibitors (see publications tab.).
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 (a spiropyrimidinetrione) and gepotidacin (an NBTI).
Structures determined include the first quinolone structure showing the important 'water-metal-ion bridge' (Wohlkonig et al., 2010; DOI: 10.1038/nsmb.1892). The table below includes many X-ray crystal structures of DNA complexes of S.aureus DNA gyase. 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 | 9fz6 2.58 | none | - | - | - | - | - | - |
P61, 94,94,411 90,90,120 |
9fz6-c1.pdb | |
4 |
6fqv 2.6 |
none |
- |
- |
- |
- |
- |
- |
P21, 93,125,155 90,96,90 |
||
5 |
5cdr 2.65 |
none |
- |
- |
- |
- |
- |
- |
P61, 93,93,411 90,90,120 |
||
6 |
5iwi 1.98 |
‘237 |
- |
- |
X |
X |
- |
- |
P61, 93,93,411 90,90,120 |
||
7 |
2xcs 2.1Å |
‘423 |
- |
- |
X |
X |
- |
P61, 93,93,413 90,90,120 |
|||
8 |
6qtk 2.31Å |
gepo' |
- |
- |
X |
X |
- |
- |
P61, 93,93,409 90,90,120 |
||
9 |
6qtp 2.37Å |
gepo' | - | - | X | X | - | - |
P21, 86,124,94 90,117,90 |
||
10 |
5iwm 2.5Å |
‘237 |
- |
- |
X |
X |
- |
- |
P61, 94,94,413 90,90,120 |
||
11 |
4bul 2.6Å |
‘587 |
- |
- |
X |
X |
- |
- |
P61, 94,94,416 90,90,120 |
||
12 |
2xcr 3.5Å |
‘423 |
- |
- |
X |
X |
- |
- |
P212121 113,165,308 90,90,90 |
||
13 |
5npp 2.22Å |
‘237 + Thp2 |
- |
- |
X |
X |
X |
X |
P61, 93,93,410 90,90,120 |
||
14 |
5npk 1.98Å |
Thp1 |
- |
- |
- |
- |
X |
X |
P21, 89,121,169 90,90.1,90 |
||
15 |
6qx1 2.65Å |
Benzois’3 |
- |
- |
- |
- |
X |
X |
P61, 93,93,409 90,90,120 |
||
16 |
6qx2 3.4 |
Benzois’3 | - | - | - | - | X | X | P21, 188, 410,94 90,120.2,90 |
Six complexes in asym. unit. Poor resolution |
|
17 |
5cdp 2.45Å |
Etop. |
X |
- |
- |
- |
- |
- |
P61, 93,93,411 90,90,120 |
||
18 |
5cdm 2.5Å |
QPT-1 |
X |
X |
- |
- |
- |
- |
P61, 94,94,412 90,90,120 |
||
19 |
8bp2 2.8Å |
zoli. |
X |
X |
- |
- |
- |
- |
P61, 95,95,417 90,90,120 |
||
20 |
5cdn 2.8Å |
Etop. |
X |
X |
- |
- |
- |
- |
P21, 90, 170, 125, 90, 102, 90 |
||
21 |
5cdq 2.95Å |
Moxi. |
X |
X |
- |
- |
- |
- |
P21, 88, 171,126, 90, 103, 90 |
||
22 |
6fqm 3.06Å |
IPY-t1 |
X |
X |
- |
- |
- |
- |
P21 88, 172, 125, 90, 103, 90 |
||
23 |
6fqS 3.11Å |
IPY-t3 |
X |
X |
- |
- |
- |
- |
P61, 94,94,420 90,90,120 |
||
24 |
5cdo 3.15Å |
QPT-1 |
X |
X |
- |
- |
- |
- |
P21, 91,170, 125, 90, 103, 90 |
||
25 |
2xct 3.35Å |
Cipro. |
X |
X |
- |
- |
- |
- |
P21, 89,123,170 90,90.3,90 90 |
2xct-v2-c2.pdb |
Footnote: ‘237 = GSK945237; ‘423 = GSK299423; gepo = geoptidacin; ‘587 = GSK966587; Thp2 = thiophene 2; Thp1 = thiophene 1; Benzois’3 = benzoisoxazole3; Etop. = etoposide; QPT-1 = QPT-1; zoli. = zoliflodacin; 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 |
Biography
I have a BSc in Physics and Chemistry from Nottingham University and a PhD in Protein Crystallography from the department of crystallography in Birkbeck College, University of London. I have a passion for using structure-guided drug design to make new medicines to improve human health; and considerable experience as an industrial structural biologist (working for GlaxoSmithKline (GSK) from 1998-2016).
I had three excellent supervisors for my PhD, Tom Blundell, Peter Lindley and Christine Slingsby, and the structure obtained, of betaB2-crystallin, was the first ‘domain swapped’ structure (Bax et al., 1990 - see Publications tab for details). Before moving to industry in 1998 I worked on structural studies on a number of proteins including: 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), the small G-protein ARF (Greasely et al., 1995) and a complex of phosducin with the beta/gamma subunits of the heterotrimeric G protein transducin (Loew et al., 1998).
I joined SmithKlineBeecham (later GlaxoSmithKline) in 1998 to work as a protein crystallographer in a newly formed structural biology group. Protein kinase structures solved included GSK-3beta (Bax et al., 2001; Christopher et al., 2009; Gentile et al., 2011, 2012; Henley et al., 2017). Crystal structures of AMPA receptor positive modulators helped advance chemistry on this challenging neuroscience target (Ward et al., 2010 a, b; Ward et al., 2011). A major area of study was new antibiotics (and anti-cancer drugs) targeting bacterial type IIA topoisomerases (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). The determination of structures of NBTIs in complexes with DNA and DNA gyrase helped the team developing gepotidacin (Gibson et al., 2019); gepotidacin is the first member of the NBTI class of antibiotic to successfully complete a phase III clinical trial.
In GSK I co-chaired the structural biology software group and was the industrial representative on the CCP4 executive committee (CCP4 is a consortium that develops crystallographic software). A talk from the 2016 CCP4 study weekend resulted in a paper entitled: ‘Getting the chemistry right: protonation, tautomers and the importance of H atoms in biological chemistry’.
I joined the Medicines Discovery Institute in Cardiff in 2018.