Dr Ben Bax

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 bB2-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 bg 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-3b (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 enter 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.

Publications

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:

1. Structure-guided drug design with a focus on diseases of the central nervous system.
2. Inhibitors of bacterial type IIA topoisomerases (fluoroquinolones, NBTIs, spiropyrimidinetriones etc.).
3. 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').

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).

Supervision

Current supervision

Past projects