Dr Benjamin Bax
(e/fe)

Darllenydd

Ysgol y Biowyddorau

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.

Date
Type

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)
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., 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)

Diddordebau ymchwil

Rwy'n fiolegydd / crisialwr strwythurol. Prif ffocws fy ymchwil yw ceisio deall sut mae cyfansoddion (moleciwlau bach) yn rhyngweithio â gweithgareddau proteinau a'u cymedroli. Nod fy ymchwil yw helpu i gefnogi cemegwyr trwy ddarparu strwythurau i gynorthwyo gyda dylunio cyffuriau dan arweiniad strwythur (gan gynnwys adnabod dyfroedd hapus ac anhapus).

Mae'r prif feysydd sydd o ddiddordeb ymchwil cyfredol yn cynnwys:

Dylunio cyffuriau dan arweiniad strwythur gyda ffocws ar glefydau'r system nerfol ganolog.
Atalyddion topoisomerases math bacteriol IIA (fflworoquinolones, NBTIs, spiropyrimidinetriones ac ati).
Otis. Oligonucleotide-adnabod atalyddion topoisomerase (gweler cyhoeddiadau tab.).

1. Dylunio cyffuriau dan arweiniad strwythur gyda ffocws ar glefydau'r system nerfol ganolog

Mae'r diddordebau'n cynnwys derbynyddion AMPA (10.1021 / jm100679e), derbynyddion NMDA a thargedau eraill.

2. Atalyddion topoisomerases math bacteriol IIA

Mae topoisomerases math IIA yn ensymau hanfodol sy'n rheoleiddio topoleg DNA trwy greu toriad DNA dwbl-sownd dwbl pedair pâr sylfaen dros dro. Mae cyfansoddion sy'n sefydlogi cyfadeiladau DNA-cleavage gyda topoisomerases math bacteriol IIA yn cynnwys y dosbarth cyffuriau fflworoquinolone hynod lwyddiannus yn ogystal â dau gyfansoddyn newydd mewn datblygiad clinigol cam hwyr, zoliflodacin (spiropyrimidinetrione) a gepotidacin (NBTI).

Mae'r strwythurau a benderfynir yn cynnwys y strwythur quinolone cyntaf sy'n dangos y 'bont dŵr-metel-ion' bwysig (Wohlkonig et al., 2010; DOI: 10.1038 / nsmb.1892). Mae'r tabl isod yn cynnwys llawer o strwythurau crisial pelydr-X o gyfadeiladau DNA o gyase DNA S.aureus. Oherwydd bod gan sawl cyfadeilad gyrase DNA S. aureus gyda DNA (Bax et al., 2019) anhwylder statig o gwmpas echel ddeublyg y 'dimer' – mae cyfesurynnau biolegol 'cyfadeiladau sengl' ar gael isod – yn nhabl 1. Gweler cyhoeddiadau dan gyfeirnod tab am fwy o fanylion.

Sylwer - mae'r strwythurau crisial gyrase DNA S.aureus hyn yn cynnwys strwythurau sydd â golygfeydd clir o safleoedd rhwymo metel-ion parth TOPRIM - ac yn awgrymu mecanwaith symud sengl ar gyfer DNA-hollti. Mae strwythur burum 2.98Å (cod pdb: 3L4K) wedi'i gymhlethu gan anhwylder statig o amgylch deublyg crisialograffig a gafodd ei fireinio'n wreiddiol gyda dau fetel ym mhob safle gweithredol wedi'i fireinio i fod yn gyson â strwythurau cydraniad uchel diamwys ac mae cyfesurynnau ar gyfer y strwythur burum mireinio hwn ar gael isod yn nhabl 2.

TABL 1 Cyfesurynnau cyfadeiladau biolegol S.aureus DNA gyrase GyrBA ymasiad trincate gyda DNA a chyfansoddion.

Mae cyfesurynnau ar gyfer cyfadeiladau 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 anhwylder deublyg o amgylch echel y cymhleth mae dau gyfadeilad ar gael, sy'n cynrychioli dau gyfeiriadedd y cymhleth biolegol a welir yn y strwythur crisial. *Noder bod gan y rhan fwyaf o'r cyfadeiladau DNA a restrir un neu ddau o gyfadeiladau yn yr uned anghymesur; ond yn y ddau adeiledd APO (2xco a 2xcq, mae'r GyrBA dimer yn eistedd ar ddeublyg crisialograffig a cheir hanner dimer yn yr uned anghymesur).

Mae'r cyfadeiladau DNA gyrase S.aureus i gyd tua C2 yn gymesur ac mae cyfansoddion wedi'u gweld mewn pedwar pocedi gwahanol: 1 (ac 1'), 2D (ar yr echelin deublyg yn y DNA), 2A (ar yr echelin deublyg rhwng y ddau is-uned GyrA), 3 (a 3').

Na	Cod PDB + cydraniad	Atalydd							Coords Crystal. (BA-x numb.), Space-group [cell (a, b, c Å, ac a,b, g °) ]	Cyfesurynnau ar gyfer cymhleth cyntaf yn asym. uned*	Cyfesurynnau ar gyfer ail gymhleth yn asym. uned*
			1	1'	2D	2A	3	3'
1	2xcq 2.98	dim	-	-	-	-	-	-	2xcq-BA-x.pdb P6₁22, 90,90,416 90,90,120	2xcq-c1.pdb
2	2xco 3.1	dim	-	-	-	-	-	-	2xco-BA-x.pdb P6₁22, 90,90,411 90,90,120	2xco-c1.pdb

3	9fz6 2.58	dim	-	-	-	-	-	-	9fz6-BA-x.pdb P6₁, 94,94,411 90,90,120	9fz6-c1.pdb
4	6fqv 2.6	dim	-	-	-	-	-	-	6fqv-BA-x.pdb P2₁, 93,125,155 90,96,90	6fqv-c1.pdb	6fqv-c2.pdb
5	5CDR 2.65	dim	-	-	-	-	-	-	5cdr-v2-BA-x.pdb (hen 5cdr-BA-x.pdb) P6₁, 93,93,411 90,90,120	5cdr-v2-c1.pdb (hen 5cdr-c1.pdb)

6	5iwi 1.98	'237	-	-	X	X	-	-	5iwi-v2-BA-x.pdb 5iwi-BA-x.pdb P6₁, 93,93,411 90,90,120	5iwi-v2-DNA-No1.pdb 5iwi-v2-DNA-No2.pdb 5iwi-c1a.pdb 5iwi-c1b.pdb
7	2xcs 2.1Å	'423	-	-	X	X	-	-	2xcs-v2-BA-x.pdb 2xcs-BA-x.pdb P6₁, 93,93,413 90,90,120	2xcs-c1a.pdb 2xcs-c1b.pdb
8	6qtk 2.31Å	gepo'	-	-	X	X	-	-	6qtk-BA-x.pdb P61, 93,93,409 90,90,120	6qtk-c1.pdb 6qtk-c2.pdb
9	6qtp 2.37Å	gepo'	-	-	X	X	-	-	6qtp-BA-x.pdb P21, 86,124,94 90,117,90	6qtp-c1.pdb 6qtp-c2.pdb
10	5iwm 2.5Å	'237	-	-	X	X	-	-	5iwm-BA-x.pdb P6₁, 94,94,413 90,90,120	5iwm-c1a.pdb 5iwm-c1b.pdb
11	4bul 2.6Å	'587	-	-	X	X	-	-	4bul-BA-x.pdb P6₁, 94,94,416 90,90,120	4bul-c1a.pdb 4bul-c1b.pdb
12	2xcr 3.5Å	'423	-	-	X	X	-	-	2xcr-BA-x.pdb P2₁2₁2_{1 113,165,308} 90,90,90	2xcr-c1a.pdb 2xcr-c1b.pdb	2xcr-c2a.pdb 2xcr-c2b.pdb

13	5npp 2.22Å	'237 + Thp2	-	-	X	X	X	X	5npp-BA-x.pdb P6₁, 93,93,410 90,90,120	5npp-c1a.pdb 5npp-c1b.pdb

14	5npk 1.98Å	Thp1	-	-	-	-	X	X	5npk-BA-x.pdb P2_1, 89,121,169 90,90.1,90	5npk-c1.pdb	5npk-c2.pdb
15	6qx1 2.65Å	Benzois'3	-	-	-	-	X	X	6qx1-BA-x.pdb P61, 93,93,409 90,90,120	6qx1-c1.pdb
16	6qx2 3.4	Benzois'3	-	-	-	-	X	X	6qx2-BA-x.pdb P21, 188, 410,94 90,120.2,90	Chwe chyfadeilad yn Asym. uned. Datrysiad gwael

17	5cdp 2.45Å	Etop.	X	-	-	-	-	-	5CDP-BA-x.pdb P6₁, 93,93,411 90,90,120	5CDP-C1.Pdb
18	5cdm 2.5Å	QPT-1	X	X	-	-	-	-	5cdm-v2-BA-x.pdb 5cdm-BA-x.pdb P6₁, 94,94,412 90,90,120	5cdm-BA-x.pdb
19	8bp2 2.8Å	zoli.	X	X	-	-	-	-	8bp2-BA-x.pdb P6₁, 95,95,417 90,90,120	8bp2-BA-x.pdb
20	5cdn 2.8Å	Etop.	X	X	-	-	-	-	5cdn-BA-x.pdb P2_1, 90, 170, 125, 90, 102, 90	5CDN-C1.Pdb	5cdn-c2.pdb
21	5cdq 2.95Å	Moxi.	X	X	-	-	-	-	5cdq-BA-x.pdb P2_1, 88, 171,126, 90, 103, 90	5cdq-c1.pdb	5cdq-c2.pdb
22	6fqm 3.06Å	IPY-T1	X	X	-	-	-	-	6fqm-BA-x.pdb P2₁ 88, 172, 125, 90, 103, 90	6fqm-c1.pdb	6fqm-c2.pdb
23	6fqS 3.11Å	IPY-T3	X	X	-	-	-	-	6fqs-BA-x.pdb P6₁, 94,94,420 90,90,120	6fqs-c1a.pdb 6fqs-c1b.pdb
24	5cdo 3.15Å	QPT-1	X	X	-	-	-	-	5cdo-BA-x.pdb P2_1, 91,170, 125, 90, 103, 90	5cdo-c1.pdb	5cdo-c2.pdb
25	2xct 3.35Å	Cipro.	X	X	-	-	-	-	2xct-v2-BA-x.pdb P2₁, 89,123,170 90,90.3,90 90	2xct-v2-c1.pdb	2xct-v2-c2.pdb

Troednodyn: '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.

Tabl 2 Cyfesurynnau cyfadeiladau biolegol ar gyfer strwythurau crisial adneuedig a mireinio 3L4K

Oherwydd bod 3L4K yn eistedd ar echel deublyg crisialograffig, mae'r dwysedd electron 2.98Å a arsylwyd i bob pwrpas yn gonvolution o ddau strwythur arwynebedd, sy'n gysylltiedig â'r echelin deublyg crisialograffig. Mae hyn yn gwneud mireinio a dehongli'r dwysedd electron yn fwy heriol, ac yn fwy amwys nag a fyddai'n digwydd ar gyfer 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 cyfadeiladau 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 ac RR-3l4k-c1a.pdb ac RR-3l4k-c1b.pdb o'r cyfesurynnau mireinio (gweler Bax et al., 2019 am fanylion).

ffeil PDB	Safle gweithredol 1	Safle gweithredol 2
	Safleoedd metel yn meddiannu	WHD Tyr 782	Safleoedd metel yn meddiannu	WHD Tyr 782'	Cyfesurynnau crisialograffig	Cyfesurynnau ar gyfer cymhleth biolegol
	A	B		A	B
3L4K gwreiddiol	1.0	1.0	Tyr	1.0	1.0	Tyr	3lk4.pdb	3lk4-c1a.pdb 3lk4-c1b.pdb
Mireinio RR-3L4K	0.5	0.5	Tyr	0.5	0.5	Tyr	RR-3l4k.pdb	RR-3l4k-c1a.pdb RR-3l4k-c1b.pdb

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.

Current supervision

Harry Morgan

Research student (with Diamond Light Source)

Contact Details

BaxB@caerdydd.ac.uk
+44 29225 11070
Y Prif Adeilad, Plas y Parc, Caerdydd, CF10 3AT

Mewnwelediadau newydd ar gyfer darganfod y genhedlaeth nesaf o wrthfiotigau

04 September 2019

Dr Benjamin Bax (e/fe)

Trosolwyg

Cyhoeddiad

2025

2024

2023