A5055669677- X-ray Diffraction in Crystallography
- Crystallization and Solubility Studies
- Cancer, Hypoxia, and Metabolism
- Epigenetics and DNA Methylation
- Antibiotic Resistance in Bacteria
- Metabolomics and Mass Spectrometry Studies
- RNA modifications and cancer
- Eicosanoids and Hypertension Pharmacology
- Prostate Cancer Treatment and Research
- Histone Deacetylase Inhibitors Research
- High Altitude and Hypoxia
- Potato Plant Research
- Mitochondrial Function and Pathology
- Pneumocystis jirovecii pneumonia detection and treatment
- Tuberculosis Research and Epidemiology
- Metal-Catalyzed Oxygenation Mechanisms
- Antibiotics Pharmacokinetics and Efficacy
- Gender Diversity and Inequality
- Plant Pathogens and Resistance
- Career Development and Diversity
- Enzyme Structure and Function
- ATP Synthase and ATPases Research
- Diversity and Career in Medicine
- Ubiquitin and proteasome pathways
- Cancer-related gene regulation
Oxford Research Group
2016-2025
University of Oxford
2015-2024
Lebanese American University
2023
Science Oxford
2016-2020
Oxfam
2017-2018
University of Leeds
2017
John Radcliffe Hospital
2017
University of Bristol
2017
MRC Weatherall Institute of Molecular Medicine
2017
Georgia Institute of Technology
2015
Four compounds in clinical trials for anaemia treatment are potent inhibitors of the hypoxia inducible factor (HIF) prolyl hydroxylases (PHDs), but differ potency and how they interact with HIF at PHD active site.
Abstract The response to hypoxia in animals involves the expression of multiple genes regulated by αβ-hypoxia-inducible transcription factors (HIFs). hypoxia-sensing mechanism oxygen limited hydroxylation prolyl residues N- and C-terminal oxygen-dependent degradation domains (NODD CODD) HIFα isoforms, as catalysed hydroxylases (PHD 1–3). Prolyl promotes binding von Hippel–Lindau protein (VHL)–elongin B/C complex, thus signalling for proteosomal HIFα. We reveal that certain PHD2 variants...
β-Lactamases are the most important mechanisms of resistance to β-lactam antibacterials. There two mechanistic classes β-lactamases: serine β-lactamases (SBLs) and zinc-dependent metallo-β-lactamases (MBLs). Avibactam, first clinically useful non-β-lactam β-lactamase inhibitor, is a broad-spectrum SBL which used in combination with cephalosporin antibiotic (ceftazidime). multiple reports on interaction avibactam SBLs but few such studies MBLs. We report biochemical biophysical binding...
Human and other animal cells deploy three closely related dioxygenases (PHD 1, 2 3) to signal oxygen levels by catalysing regulated prolyl hydroxylation of the transcription factor HIF. The discovery HIF prolyl-hydroxylase (PHD) enzymes as sensors raises a key question existence nature non-HIF substrates, potentially transducing biological responses hypoxia. Over 20 such substrates are reported. We therefore sought characterise their reactivity with recombinant PHD enzymes. Unexpectedly, we...
Abstract Altered central carbon metabolism is a hallmark of many diseases including diabetes, obesity, heart disease and cancer. Identifying metabolic changes will open opportunities for better understanding aetiological processes identifying new diagnostic, prognostic, therapeutic targets. Comprehensive robust analysis primary pathways in cells, tissues bio-fluids, remains technically challenging. We report on the development validation highly reproducible untargeted method using...
NMR-filtered virtual screening led to the identification of non-Zn(<sc>ii</sc>)-chelating metallo-β-lactamase inhibitors, which mimic interactions made by bicyclic β-lactam antibiotic substrates as they initially bind enzymes.
Abstract Ivosidenib, an inhibitor of isocitrate dehydrogenase 1 (IDH1) R132C and R132H variants, is approved for the treatment acute myeloid leukaemia (AML). Resistance to ivosidenib due a second site mutation IDH1 R132C, leading R132C/S280F, has emerged. We describe biochemical, crystallographic, cellular studies on R132C/S280F R132H/S280F variants that inform mechanism second-site resistance, which involves both modulation binding at dimer-interface alteration kinetic properties, enable...
Significance The plant-signaling molecule ethylene is biosynthesized from 1-aminocyclopropane-1-carboxylic acid (ACC), as catalyzed by ACC oxidase, which homologous to the 2-oxoglutarate (2OG) oxygenases, but does not use a 2OG cosubstrate. Bacteria produce in highly unusual reaction that involves oxidative fragmentation. Biophysical studies on Pseudomonas ethylene-forming enzyme (EFE) reveal how structural and stereoelectronic factors enable EFE bias away normal oxygenase catalysis...
Abstract Endocrine resistance (EnR) in advanced prostate cancer is fatal. EnR can be mediated by androgen receptor (AR) splice variants, with AR variant 7 (AR-V7) arguably the most clinically important variant. In this study, we determined proteins key to generating AR-V7, validated our findings using clinical samples, and studied splicing regulatory mechanisms models. Triangulation studies identified JMJD6 as a regulator of evidenced its upregulation vitro EnR, downregulation alongside...
ABSTRACT Metallo-β-lactamases (MBLs) are of increasing clinical significance; the development clinically useful MBL inhibitors is challenged by rapid evolution variant MBLs. The Verona integron-borne metallo-β-lactamase (VIM) enzymes among most widely distributed MBLs, with >40 VIM variants having been reported. We report on crystallographic analysis VIM-5 and comparison biochemical biophysical properties VIM-1, VIM-2, VIM-4, VIM-5, VIM-38. Recombinant were produced purified, their...
Zinc ion-dependent β-lactamases (MBLs) catalyze the hydrolysis of almost all β-lactam antibiotics and resist action clinically available β-lactamase inhibitors. We report how application in silico fragment-based molecular design employing thiol-mediated metal anchorage leads to potent MBL The new inhibitors manifest inhibition important B1 subfamily MBLs, including widespread NDM-1, IMP-1, VIM-2 enzymes; with lower potency, some them also inhibit relevant Class A D serine-β-lactamases. show...
The binding of prolyl-hydroxylated HIF-α to PHD2 is hindered by prior 2OG binding; likely, leading the inhibition degradation under limiting conditions.
Isocitrate dehydrogenase (IDH) 1/2 gain-of-function variants catalyze the production of oncometabolite 2-hydroxyglutarate and are validated targets for leukemia treatment. We report binding inhibition studies on 13 IDH1/2 variant inhibitors, including clinical candidates drugs, with wild-type (wt) IDH1 its cancer-associated variant, R132H. Interestingly, all inhibitors bind wt despite not, or only weakly, inhibiting it. Selective R132H over does not principally relate to affinities resting...
We report the development of a potent and selective de novo cyclic peptide ligand for epigenetic methyllysine reader domain. The binds at aromatic cage PHD-finger modulates JmjC lysine demethylase activity KDM7.
Abstract The mechanism of Amifostine (WR-2721) mediated radioprotection is poorly understood. effects amifostine on human basal metabolism, mouse liver metabolism and normal tumor hepatic cells were studied. Indirect calorimetric canopy tests showed significant reductions in oxygen consumption carbon dioxide emission cancer patients receiving amifostine. Glucose levels significantly decreased lactate increased patient venous blood. Although vitro did not inhibit the activity...
Crystallographic analyses of the VIM-5 metallo-β-lactamase (MBL) with isoquinoline inhibitors reveal non zinc ion binding modes. Comparison other MBL-inhibitor structures directed addition a zinc-binding thiol enabling identification potent B1 MBL inhibitors. The potentiate meropenem activity against clinical isolates harboring MBLs.
Tight, non-active site binding cyclic peptides are promising affinity reagents for studying proteins and their interactions.
Fe(II)- and 2-oxoglutarate (2OG)-dependent JumonjiC domain-containing histone demethylases (JmjC KDMs) are "epigenetic eraser" enzymes involved in the regulation of gene expression emerging drug targets oncology. We screened a set clinically used iron chelators report that they potently inhibit JMJD2A (KDM4A) vitro. Mode action investigations revealed one compound, deferasirox, is bona fide active site-binding inhibitor as shown by kinetic spectroscopic studies. Synthesis derivatives with...