A5053440553- Synthesis and Catalytic Reactions
- Biochemical and Molecular Research
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Asymmetric Synthesis and Catalysis
- Chemical Synthesis and Analysis
- Synthesis and Reactivity of Sulfur-Containing Compounds
- Synthesis of heterocyclic compounds
- Synthesis and Biological Evaluation
- Antibiotic Resistance in Bacteria
- Synthesis and Reactions of Organic Compounds
- Organic Chemistry Cycloaddition Reactions
- RNA and protein synthesis mechanisms
- Catalytic C–H Functionalization Methods
- Cancer therapeutics and mechanisms
- Cyclopropane Reaction Mechanisms
- Fluorine in Organic Chemistry
- Click Chemistry and Applications
- HIV/AIDS drug development and treatment
- Bacterial Genetics and Biotechnology
- Synthesis of β-Lactam Compounds
- Computational Drug Discovery Methods
- Fibroblast Growth Factor Research
- Oxidative Organic Chemistry Reactions
- Synthetic Organic Chemistry Methods
University of Leeds
2015-2024
Institute of Structural and Molecular Biology
2009-2023
John Radcliffe Hospital
2017
University of Oxford
2017
University of Bristol
2001-2017
MRC Weatherall Institute of Molecular Medicine
2017
University of York
2014
Cambridge University Press
2014
University of Surrey
2012
University of Hull
2006
The hierarchical self-assembly of rationally designed synthetic peptides into β-sheet tapes, ribbons, fibrils, and fibers opens up potentially useful routes to soft−solidlike materials such as hydrogels, organogels, or liquid crystals. Here, it is shown how incorporation Glu (−CH2CH2COOH) Orn (−CH2CH2CH2NH2) the primary structure an 11 amino acid peptide enables be rapidly (seconds) reversibly controlled by simply changing pH. Solutions monomeric peptide, typically at concentrations in...
Abstract β-Lactamases enable resistance to almost all β-lactam antibiotics. Pioneering work revealed that acyclic boronic acids can act as ‘transition state analogue’ inhibitors of nucleophilic serine enzymes, including serine-β-lactamases. Here we report biochemical and biophysical analyses revealing cyclic boronates potently inhibit both zinc-dependent β-lactamases by a mechanism involving mimicking the common tetrahedral intermediate. Cyclic also non-essential penicillin-binding protein...
ABSTRACT High-risk human papillomavirus type 16 (HPV16) is the primary causative agent of cervical cancer and therefore responsible for significant morbidity mortality worldwide. Cellular transformation mediated directly by expression viral oncogenes, least characterized which, E5, subverts cellular proliferation immune recognition processes. Despite a growing catalogue E5-specific host interactions, little understood regarding molecular basis its function. Here we describe novel function...
Metallo-β-lactamases (MBLs) are a growing threat to the use of almost all clinically used β-lactam antibiotics. The identification broad-spectrum MBL inhibitors is hampered by lack suitable screening platform, consisting appropriate substrates and set relevant MBLs. We report procedures for preparation metallo-β-lactamases (i.e., NDM-1 (New Delhi MBL), IMP-1 (Imipenemase), SPM-1 (São Paulo VIM-2 (Verona integron-encoded MBL)) fluorogenic (umbelliferone-derived cephalosporins). were compared...
β-Lactamase-mediated resistance is a growing threat to the continued use of β-lactam antibiotics. The β-lactam-based serine-β-lactamase (SBL) inhibitors clavulanic acid, sulbactam, and tazobactam and, more recently, non-β-lactam inhibitor avibactam has extended utility β-lactams against bacterial infections demonstrating via these enzymes. These molecules are, however, ineffective metallo-β-lactamases (MBLs), which catalyze their hydrolysis. To date, there are no clinically available...
Molecular Dynamics (MD) simulations have been used to obtain a molecular insight into the origins of twist, bend, and helix pitch tape-like ribbon (double tape)-like β-sheet aggregates formed by self-assembling peptides P11-I (CH3CO-QQRQQQQQEQQ-NH2) P11-II (CH3CO-QQRFQWQFEQQ-NH2). differs from in that glutamines at positions 4, 6, 8 substituted for F, W, this gives rise left-handed helicoidal tapes having significantly shorter pitch. The presence these hydrophobic residues also enhances...
Self-assembled tapes: Adsorption and self-assembly of peptides on mica substrates produces tapes, a single molecule in thickness, with cross-β-sheet structure (see picture). A variety surface morphologies may be produced depending the preparation procedure. One these, close-packed monolayer parallel-aligned practical utility as functionalized protein-like surface. Supporting information for this article is available WWW under http://www.wiley-vch.de/contents/jc_2002/2005/z462160_s.pdf or...
The adaptive and further evolutionary responses of Staphylococcus aureus to selection pressure with the antibiotic rifampin have not been explored in detail. We now present a detailed analysis these systems. use for chemotherapy infections caused by S. has resulted mutants alterations within beta subunit target enzyme, RNA polymerase. Using new collection strains, we identified numerous novel mutations subunits both clinical vitro-derived resistant strains established that additional,...
D-cycloserine is an antibiotic which targets sequential bacterial cell wall peptidoglycan biosynthesis enzymes: alanine racemase and D-alanine:D-alanine ligase. By a combination of structural, chemical mechanistic studies here we show that the inhibition ligase by proceeds via distinct phosphorylated form drug. This insight reveals bimodal mechanism action for single on different enzyme has significance design future inhibitor molecules based this structure.
Deep-blue luminescent [{Ir(C^N)<sub>2</sub>}<sub>3</sub>(L)<sub>2</sub>]<sup>3+</sup> coordination cages with structurally integral pyridyl-azo-phenyl groups can be reversibly photo-isomerised no compositional change.
The hydantoin transporter Mhp1 is a sodium-coupled secondary active transport protein of the nucleobase-cation-symport family and member widespread 5-helix inverted repeat superfamily transporters. structure was previously solved in three different conformations providing insight into molecular basis alternating access mechanism. Here, we elucidate detailed events substrate binding, through combination crystallography, dynamics, site-directed mutagenesis, biochemical/biophysical assays,...
Staphylococcus aureus and a number of other Gram-positive organisms harbour two genes (murA murZ) encoding UDP-N-acetylglucosamine enolpyruvyl transferase activity for catalysing the first committed step peptidoglycan biosynthesis. We independently inactivated murA murZ in S. established that either can sustain viability. Purification characterization MurA MurZ enzymes indicated they are biochemically similar vitro, consistent with overall structures predicted isozymes by molecular...
Pyrimidine biosynthesis is an attractive drug target in a variety of organisms, including humans and the malaria parasite Plasmodium falciparum. Dihydroorotate dehydrogenase, enzyme catalyzing only redox reaction pyrimidine pathway, well-characterized for chemotherapeutical intervention. In this study, we have applied SPROUT-LeadOpt, software package structure-based discovery lead optimization, to improve binding active metabolite anti-inflammatory leflunomide cavities P. falciparum human...
Transient Receptor Potential Melastatin 3 (TRPM3) is a widely expressed calcium-permeable non-selective cation channel that stimulated by high concentrations of nifedipine or physiological steroids include pregnenolone sulphate. Here we sought to identify inhibit TRPM3. Channel activity was studied using calcium-measurement and patch-clamp techniques. Progesterone (0.01-10μM) suppressed TRPM3 evoked metabolites 17β-oestradiol were also inhibitory but the effects relatively small....
Oxazolidinone and pleuromutilin antibiotics are currently used in the treatment of staphylococcal infections. Although both inhibit protein synthesis have overlapping binding regions on 23S rRNA, potential for cross-resistance between two classes through target site mutations has not been thoroughly examined. Mutants Staphylococcus aureus resistant to linezolid were selected found exhibit tiamulin, a member class antibiotics. However, resistance was unidirectional because mutants S. tiamulin...
Abstract: The hepatitis C virus (HCV) p7 ion channel plays a critical role during infectious production and represents an important new therapeutic target. Its activity is blocked by structurally distinct classes of small molecules, with sensitivity varying between isolate sequences. Although this indicative specific protein–drug interactions, lack high-resolution structural information has precluded the identification inhibitor binding sites, their modes action remain undefined....
Hepatitis C virus (HCV) chronically infects 170 million individuals, causing severe liver disease. Although antiviral chemotherapy exists, the current regimen is ineffective in 50% of cases due to high levels innate resistance. New, virus-specific therapies are forthcoming although their development has been slow and they few number, driving search for new drug targets. The HCV p7 protein forms an ion channel vitro critical secretion infectious virus. displays sensitivity several classes...
ABSTRACT A collection of rifampin-resistant mutants Staphylococcus aureus with characterized RNA polymerase β-subunit ( rpoB ) gene mutations was cross-screened against a number other inhibitors to correlate susceptibility specific genotypes. The were cross-resistant streptolydigin and sorangicin A. In contrast, thiolutin, holomycin, corallopyronin A, ripostatin retained activity the mutants. second group may be interest as drug development candidates.
ABSTRACT Chromosomal resistance to mupirocin in clinical isolates of Staphylococcus aureus arises from V 588 F or 631 mutations isoleucyl-tRNA synthetase (IRS). Whether these are the only IRS that confer simply those survive clinic is unknown. Mupirocin-resistant mutants S. 8325-4 were therefore generated examine their ileS genotypes and vitro vivo fitness costs associated with them before after compensatory evolution. Most spontaneous first-step mupirocin-resistant carried IRS, but a new...