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Dr Benjamin Bax
(e/fe)
Timau a rolau for Benjamin Bax
Darllenydd
Ysgol y Biowyddorau
Trosolwyg
Rwy'n Ddarllenydd mewn Bioleg Strwythurol yn y Sefydliad Darganfod Meddyginiaethau ym Mhrifysgol Caerdydd. Nod y Sefydliad yw cyfieithu dealltwriaeth o fecanweithiau clefydau i 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.
Gweithiais i GlaxoSmithKline am ddeunaw mlynedd (1998-2016); cefnogi timau prosiect gyda data strwythurol, ar ystod o niwrowyddoniaeth, gwrthficrobaidd a thargedau eraill, gan gynnwys modiwlyddion positif derbynyddion AMPA (Ward, Bax a Harries, 2010; DOI: 10.1111 / j.1476-5381.2010.00726.x)
Fe wnes i gefnogi'r tîm a ddatblygodd y gwrthfiotig newydd gepotidacin gyda data strwythurol (Bax, et al., 2010 Nature, 466, tt. 935-940) ac wedi cyhoeddi llawer o strwythurau grisial o gymhlethdodau DNA o DNA-gyrase a chyfansoddion (gweler tabl 1 ar Ymchwil tab - a chyhoeddiadau). Mae strwythurau'n awgrymu bod moleciwlau bach hyblyg yn aml yn gwneud atalyddion gwell o'r targed cyffuriau hyblyg hwn (cymhleth protein/DNA) na moleciwlau bach mwy anhyblyg.
Cyhoeddiad
2025
- Kocsy, K. et al., 2025. Gene editing for collagen disorders: current advances and future perspectives. Gene Therapy 32 , pp.676-689. (10.1038/s41434-025-00560-7)
- Nicholls, R. A. et al., 2025. How do gepotidacin and zoliflodacin stabilize DNA-cleavage complexes with bacterial type IIA topoisomerases? 2. A single moving metal mechanism. International Journal of Molecular Sciences 26 (1) 33. (10.3390/ijms26010033)
2024
- Wever, M. et al., 2024. Structure-based discovery of first inhibitors targeting the helicase activity of human PIF1. Nucleic Acids Research 52 (20), pp.12616-12632. (10.1093/nar/gkae897)
- Morgan, H. et al. 2024. How do Gepotidacin and Zoliflodacin stabilize DNA cleavage complexes with bacterial Type IIA topoisomerases? 1. Experimental definition of metal binding sites. International Journal of Molecular Sciences 25 (21) 11688. (10.3390/ijms252111688)
2023
- Byl, J. A. W. et al., 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) 1634. (10.3390/ijms24021634)
2022
- Bax, B. D. et al. 2022. Oligonucleotide-recognizing topoisomerase inhibitors (OTIs): precision gene editors for neurodegenerative diseases. International Journal of Molecular Sciences 23 (19) 11541. (10.3390/ijms231911541)
- Elvers, K. T. et al. 2022. Structures of the human SPAK and OSR1 conserved C-terminal (CCT) domains. ChemBioChem 23 (1) e202100441. (10.1002/cbic.202100441)
2020
- Fenn, G. et al. 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. et al., 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. et al. 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. et al., 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. et al., 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. et al., 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. et al., 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 10048. (10.1038/ncomms10048)
- 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)
- 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)
- 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. et al., 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. et al., 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. et al., 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. et al., 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. et al., 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. 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)
- Loew, A. et al., 1998. Phosducin induces a structural change in transducin ??. Structure 6 (8), pp.1007-1019. (10.1016/S0969-2126(98)00102-6)
1997
- Bax, B. et al. 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. et al., 1997. Common themes and surprising differences in small G-proteins. Biochemical Society Transactions 25 (3), pp.989-991. (10.1042/bst0250989)
1996
- Srinivasan, N. et al., 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. et al., 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. et al., 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. et al., 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. et al. 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. et al., 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. et al., 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. et al., 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. et al., 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
- Kocsy, K. et al., 2025. Gene editing for collagen disorders: current advances and future perspectives. Gene Therapy 32 , pp.676-689. (10.1038/s41434-025-00560-7)
- Nicholls, R. A. et al., 2025. How do gepotidacin and zoliflodacin stabilize DNA-cleavage complexes with bacterial type IIA topoisomerases? 2. A single moving metal mechanism. International Journal of Molecular Sciences 26 (1) 33. (10.3390/ijms26010033)
- Wever, M. et al., 2024. Structure-based discovery of first inhibitors targeting the helicase activity of human PIF1. Nucleic Acids Research 52 (20), pp.12616-12632. (10.1093/nar/gkae897)
- Morgan, H. et al. 2024. How do Gepotidacin and Zoliflodacin stabilize DNA cleavage complexes with bacterial Type IIA topoisomerases? 1. Experimental definition of metal binding sites. International Journal of Molecular Sciences 25 (21) 11688. (10.3390/ijms252111688)
- Byl, J. A. W. et al., 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) 1634. (10.3390/ijms24021634)
- Bax, B. D. et al. 2022. Oligonucleotide-recognizing topoisomerase inhibitors (OTIs): precision gene editors for neurodegenerative diseases. International Journal of Molecular Sciences 23 (19) 11541. (10.3390/ijms231911541)
- Elvers, K. T. et al. 2022. Structures of the human SPAK and OSR1 conserved C-terminal (CCT) domains. ChemBioChem 23 (1) e202100441. (10.1002/cbic.202100441)
- Fenn, G. et al. 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. et al., 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. et al. 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. et al., 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. et al., 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. et al., 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. et al., 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 10048. (10.1038/ncomms10048)
- 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)
- 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)
- 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. et al., 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. et al., 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)
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Ymchwil
Diddordebau ymchwil
Rwy'n fiolegydd strwythurol/crisialogydd. Prif ffocws fy ymchwil yw ceisio deall sut mae cyfansoddion (moleciwlau bach) yn rhyngweithio â gweithgareddau proteinau ac yn cymedroli. Nod fy ymchwil yw helpu i gefnogi cemegwyr trwy ddarparu strwythurau i gynorthwyo i ddylunio cyffuriau dan arweiniad strwythur (gan gynnwys adnabod dyfroedd hapus ac anhapus).
Mae'r prif feysydd o ddiddordeb ymchwil ar hyn o bryd yn cynnwys:
- Dylunio cyffuriau dan arweiniad strwythur gyda ffocws ar glefydau'r system nerfol ganolog.
- Atalyddion topoisomerases math IIA bacteriol (fluoroquinolones, NBTIs, spiropyrimidinetriones ac ati).
- OTIs. Atalyddion topoisomerase sy'n cydnabod oligonucleotidau (gweler tab cyhoeddiadau).
1. Dyluniad cyffuriau dan arweiniad strwythur gyda ffocws ar glefydau'r system nerfol ganolog
Mae'r diddordebau yn cynnwys derbynyddion AMPA (10.1021 / jm100679e), derbynyddion NMDA a thargedau eraill. Mae'r derbynnydd AMPA PAM DT-101 ar hyn o bryd mewn treial clinigol cam II ar gyfer anhwylder iselder mawr ( https://clinicaltrials.gov/study/NCT07300969 ).
2. Atalyddion topoisomerases math IIA bacteriol (neu sydd â'r proffil cynnyrch targed cywir - targedu deuol).
Mae topoisomerases math IIA yn ensymau hanfodol sy'n rheoleiddio topoleg DNA trwy greu toriad DNA dwbl dros dro. Mae cyfansoddion sy'n sefydlogi cymhlethdodau hollti DNA gyda topoisomerases math IIA bacteriol yn cynnwys y dosbarth fflworquinolone hynod lwyddiannus o gyffuriau (sydd â rhybuddion 'blwch du' yn UDA) yn ogystal â chyffuriau cymeradwy 2025, zoliflodacin (spiropyrimidinetrione) a gepotidacin (NBTI - patent gyntaf gan GlaxoSmithKline yn 2008) (gweler Osheroff, 2026; DOI: 10.3390 / ijms27010496). Sylwer, er bod NBTI yn wreiddiol yn sefyll am novel bacterial topoisomerase inhibitor - mae'n well gennym bellach fod yr acronym NBTI ar gyfer nsafleoedd hollti ar DNA binding ar yr echel twofold inhibitor.
Mae'r strwythurau a bennwyd yn cynnwys y strwythur quinolone cyntaf sy'n dangos y 'bont dŵr-metel-ïon' bwysig (Wohlkonig et al., 2010; DOI: 10.1038/nsmb.1892). Sylwch fod y ddau quinolones a spiropyrimidinetriones yn rhwymo yn y ddau, ar gyfer safleoedd hollti DNA staggered pâr sylfaen.
Mae'r tabl isod yn cynnwys llawer o strwythurau crisial pelydr-X o gymhlethdodau DNA S.aureus DNA gyase. Oherwydd bod sawl cymhleth gyrase DNA S. aureus gyda DNA (Bax et al., 2019; Morgan et al., 2024) anhwylder statig o amgylch echel ddeublyg y 'dimer' – mae cyfesurynnau biolegol 'cymhlethdodau sengl' ar gael isod – yn nhabl 1. Gweler y cyhoeddiadau o dan y tab cyfeirio am ragor o fanylion.
Sylwer - mae'r strwythurau crisial gyrase DNA S.aureus hyn yn cynnwys strwythurau sydd â golygfeydd clir o safleoedd rhwymo ïonau metel parth TOPRIM - ac yn awgrymu un mecanwaith symudol ar gyfer hollti DNA. Mae strwythur burum 2.98Å (cod pdb: 3L4K) wedi'i gymhlethu gan anhrefn statig o amgylch deublyg crisialog a mireinio yn wreiddiol gyda dau fetel ym mhob safle gweithredol wedi'i ail-fireinio i fod yn gyson â strwythurau cydraniad uchel anghyffredin ac mae cyfesurynnau ar gyfer y strwythur burum wedi'i ailfireinio ar gael isod yn nhabl 2.
TABL 1 Cyfesurynnau cymhlethdodau biolegol S.aureus DNA gyrase GyrBA fusion truncate gyda DNA a chyfansoddion.
Mae cyfesurynnau ar gyfer cymhlethdodau biolegol ar gael (cliciwch i uwchlwytho) yn y colofnau sydd wedi'u labelu 'Cyfesurynnau ar gyfer cymhleth cyntaf (neu ail) mewn uned anghymesur'. Sylwch fod y cynllun rhifo a ddefnyddir yn wahanol i rifo PDB. Os oes gan y cymhleth anhrefn deublyg o amgylch echel y cymhleth, mae dau gymhleth ar gael, sy'n cynrychioli dau gyfeiriadedd y cymhleth biolegol a welir yn y strwythur grisial. *Sylwch fod gan y rhan fwyaf o'r cymhlethdodau DNA a restrir un neu ddau gymhleth yn yr uned anghymesur; ond yn y ddau strwythur apo (2xco a 2xcq, mae'r dimer GyrBA yn eistedd ar ddeublyg crisialog ac mae hanner dimer yn yr uned anghymesur).
Mae'r cymhlethdodau DNA gyrase S.aureus i gyd yn fras C2 cymesur ac mae cyfansoddion wedi'u harsylwi mewn pedwar poced gwahanol: 1 (ac 1'), 2D (ar yr echel ddwywaith yn y DNA), 2A (ar yr echel ddeublyg rhwng y ddwy is-uned GyrA), 3 (a 3').
| Na |
Cod PDB + Cydraniad |
Atalydd | Cydlyniadau grisial. (BA-x numb.), Grŵp gofod [cell (a,b,c Å, ac a,b,g °)] | Cyfesurynnau ar gyfer y cymhleth cyntaf mewn asym. uned* | Cyfesurynnau ar gyfer yr ail gymhleth mewn asym. uned* | ||||||
|
1 |
1' |
2D |
2A |
3 |
3' |
||||||
|
1 |
2xcq 2.98 |
dim |
- |
- |
- |
- |
- |
- |
P6122, 90,90,416 90,90,120 |
||
|
2 |
2xco 3.1 |
dim |
- |
- |
- |
- |
- |
- |
P6122, 90,90,411 90,90,120 |
||
| 3 | 9fz6 2.58 | dim | - | - | - | - | - | - |
P61, 94,94,411 90,90,120 |
9fz6-c1.pdb | |
|
4 |
6FQV 2.6 |
dim |
- |
- |
- |
- |
- |
- |
P21, 93,125,155 90,96,90 |
||
|
5 |
5cdr 2.65 |
dim |
- |
- |
- |
- |
- |
- |
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 |
4bwl 2.6Å |
'587 |
- |
- |
X |
X |
- |
- |
P61, 94,94,416 90,90,120 |
||
|
12 |
2xcr 3.5Å |
'423 |
- |
- |
X |
X |
- |
- |
P21 2121 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 |
THP1color |
- |
- |
- |
- |
X |
X |
P21, 89,121,169 90,90.1,90 |
||
|
15 |
6qx1color 2.65Å |
Benzois'3 |
- |
- |
- |
- |
X |
X |
P61, 93,93,409 90,90,120 |
||
| 16 |
6qx2color 3.4 |
Benzois'3 | - | - | - | - | X | X | P21, 188, 410,94 90,120.2,90 |
Chwe chymhleth yn asym. uned. Cydraniad gwael |
|
|
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 |
Troednodyn: '237 = GSK945237; '423 = GSK299423; gepo = geoptidacin; '587 = GSK966587; Thp2 = thiophene 2; Thp1 = thiophene 1; Benzois'3 = benzoisoxazole3; Etop. = etoposid; QPT-1 = QPT-1; zoli. = zoliflodacin; Moxi. = moxifloxacin; IPY-t1 = imidazopyrazinone-tricyclic 1; ; IPY-t3 = imidazopyrazinone-tricyclic 3; cipro = ciprofloxacin.
Tabl 2 Cyfesurynnau cymhlethdodau biolegol ar gyfer strwythurau grisial 3L4K wedi'u hadneuo a'u hail-fireinio
Oherwydd bod 3L4K yn eistedd ar echel ddeublyg crisialog, mae'r dwysedd electron 2.98Å a arsylwir yn effeithiol yn gyfuniad o ddau strwythur wedi'u gorosod, sy'n gysylltiedig â'r echel ddeublyg grisialog. Mae hyn yn gwneud mireinio a dehongli dwysedd yr electronau yn fwy heriol, ac yn fwy amwys nag y byddai'n wir am strwythur grisial pelydr-X 2.98Å nad yw'n dioddef o anhwylder statig o'r fath. Isod cyflwynir cyfesurynnau o'r ddau ddehongliad o'r data: 3lk4.pdb a'r cymhlethdodau sy'n deillio, 3l4k-c1a.pdb a 3l4k-c1b.pdb yw'r dehongliad a gyhoeddwyd yn wreiddiol (Schmidt et al., 2010), tra bod RR-3l4k.pdb a RR-3l4k-c1a.pdb a RR-3l4k-c1b.pdb yn dod o'r cyfesurynnau ail-fireinio (gweler Bax et al., 2019 am fanylion).
| Ffeil PDB | Safle gweithredol 1 | Safle gweithredol 2 | ||||||
|---|---|---|---|---|---|---|---|---|
|
Meddiannaeth safle metel |
WHD Tyr 782 |
Meddiannaeth safle metel |
WHD Tyr 782' |
Cyfesurynnau crisialog |
Cyfesurynnau ar gyfer cymhleth biolegol |
|||
|
A |
B |
A |
B |
|||||
|
Gwreiddiol 3L4K |
1.0 |
1.0 |
Tŷ |
1.0 |
1.0 |
Tŷ | ||
|
Ail-fireinio RR-3L4K |
0.5 |
0.5 |
Tŷ |
0.5 |
0.5 |
Tŷ |
Bywgraffiad
Ymunais â SmithKlineBeecham (GlaxoSmithKline yn ddiweddarach) ym 1998 i weithio fel crisialog protein mewn grŵp bioleg strwythurol sydd newydd ei ffurfio. Roedd strwythurau protein kinase a ddatryswyd yn cynnwys GSK-3beta (Bax et al., 2001; Christopher et al., 2009; Gentile et al., 2011, 2012; Henley et al., 2017). Helpodd strwythurau grisial modulators positif derbynnydd AMPA i hyrwyddo cemeg ar y targed niwrowyddoniaeth heriol hwn (Ward et al., 2010 a, b; Ward et al., 2011). Prif faes astudiaeth yw gwrthfiotigau newydd sy'n targedu topoisomerases math IIA 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; Morgan et al., 2023, Morgan et al., 2024, Nicholls et al., 2025). Helpodd strwythur cymhleth hollti DNA o'r gwrthfiotig zoliflodacin newydd i ddeall sut mae'r gwrthfiotig newydd hwn yn gweithio (Morgan et al., 2023) wrth bennu strwythurau S. Aureus Helpodd gyrase / DNA DNA y tîm i ddatblygu gepotidacin (Gibson et al., 2019)
Yn GSK roeddwn i'n cyd-gadeirio'r grŵp meddalwedd bioleg strwythurol ac roeddwn i'n gynrychiolydd diwydiannol ar bwyllgor gweithredol CCP4 (mae CCP4 yn gonsortiwm sy'n datblygu meddalwedd crisialogeg). Arweiniodd sgwrs o benwythnos astudiaeth 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.
Mae gen i BSc mewn Ffiseg a Chemeg o Brifysgol Nottingham a PhD mewn Crisialog Protein o'r adran crisialog yng Ngholeg Birkbeck, Prifysgol Llundain. Mae gen i angerdd dros ddefnyddio dylunio cyffuriau dan arweiniad strwythur i wneud meddyginiaethau newydd i wella iechyd pobl; a phrofiad sylweddol fel biolegydd strwythurol diwydiannol (yn gweithio i GlaxoSmithKline (GSK) o 1998-2016).
Y strwythur ar gyfer fy PhD, o betaB2-crisialog, oedd y strwythur 'cyfnewid parth' cyntaf (Bax et al., 1990 - gweler y tab Cyhoeddiadau am fanylion). Cyn symud i'r diwydiant ym 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), yr ARF G-protein bach (Greasely et al., 1995) a chymhleth o ffosducin gydag is-unedau beta / gamma y transducin protein G heterotrimerig (Loew et al., 1998).