A5006860079- Biochemical and Molecular Research
- HIV Research and Treatment
- HIV/AIDS drug development and treatment
- Virus-based gene therapy research
- Bacterial Genetics and Biotechnology
- Enzyme Structure and Function
- Bacteriophages and microbial interactions
- Virology and Viral Diseases
- CRISPR and Genetic Engineering
- Vibrio bacteria research studies
- Salmonella and Campylobacter epidemiology
- Protein purification and stability
- Cancer Research and Treatments
- Hemoglobin structure and function
- RNA and protein synthesis mechanisms
- Medical Imaging and Pathology Studies
- RNA modifications and cancer
- Iron Metabolism and Disorders
- Protein Structure and Dynamics
- Radiopharmaceutical Chemistry and Applications
- Genomics and Phylogenetic Studies
- DNA and Nucleic Acid Chemistry
- Cytomegalovirus and herpesvirus research
- Neonatal Health and Biochemistry
- Antimicrobial Peptides and Activities
University of Sussex
2021-2024
Brunel University of London
2023
Imperial College London
2008-2018
National Institutes of Health
2011
National Cancer Institute
2011
Frederick National Laboratory for Cancer Research
2011
Center for Cancer Research
2011
University College London
2006-2007
Birkbeck, University of London
2006-2007
Institute of Structural and Molecular Biology
2006
The development of HIV integrase (IN) strand transfer inhibitors (INSTIs) and our understanding viral resistance to these molecules have been hampered by a paucity available structural data. We recently reported cocrystal structures the prototype foamy virus (PFV) intasome with raltegravir elvitegravir, establishing general INSTI binding mode. now present an expanded set containing PFV intasomes complexed first- second-generation INSTIs at resolutions up 2.5 Å. Importantly, improved...
Raltegravir (RAL) and related HIV-1 integrase (IN) strand transfer inhibitors (INSTIs) efficiently block viral replication in vitro suppress viremia patients. These small molecules bind to the IN active site, causing it disengage from deoxyadenosine at 3′ end of DNA. The emergence strains that are highly resistant RAL underscores pressing need develop INSTIs with improved resistance profiles. Herein, we show candidate second-generation drug dolutegravir (DTG, S/GSK1349572) effectively...
The intasome is the basic recombination unit of retroviral integration, comprising integrase protein and ends viral DNA made by reverse transcription. Clinical inhibitors preferentially target DNA-bound form as compared with free protein, highlighting critical requirement for detailed understanding HIV-1 structure function. Although previous biochemical studies identified residues that contact DNA, structural details protein–protein protein–DNA interactions within functional were lacking....
Lens epithelium derived growth factor (LEDGF), also known as PC4 and SFRS1 interacting protein 1 (PSIP1) transcriptional co-activator p75, is the cellular binding partner of lentiviral integrase (IN) proteins. LEDGF accounts for characteristic propensity Lentivirus to integrate within active transcription units required efficient viral replication. We now present a crystal structure containing N-terminal catalytic core domains (NTD CCD) HIV-2 IN in complex with domain (IBD) LEDGF. The...
Significance Transportin 3 (Tnpo3) was shown to orchestrate nuclear import of splicing factors over a decade ago, but how it recognizes these cargoes remained unknown. Furthermore, the recently discovered role for Tnpo3 as cofactor HIV-1 replication requires mechanistic clarification. We show that associates with wide range proteins involved in mRNA metabolism, majority which contain serine/arginine-rich domains. Using X-ray crystallography we determined three-dimensional structures its key...
Non-typhoidal Salmonella strains are responsible for invasive infections associated with high mortality and recurrence in sub-Saharan Africa, there is strong evidence clonal relapse following antibiotic treatment. Persisters non-growing bacteria that thought to be the recalcitrance of many antibiotics. Toxin-antitoxin systems stress-responsive elements important persister formation, specifically during infection. Here, we report analysis formation clinical Typhimurium Enteritidis human...
Establishment of the stable provirus is an essential step in retroviral replication, orchestrated by integrase (IN), a virus-derived enzyme. Until now, available structural information was limited to INs human immunodeficiency virus type 1 (HIV-1), avian sarcoma (ASV) and their close orthologs from Lentivirus Alpharetrovirus genera. Here, we characterized vitro activity prototype foamy (PFV) IN Spumavirus genus determined three-dimensional structure its catalytic core domain (CCD)....
Experimental evidence suggests that a tetramer of integrase (IN) is the protagonist concerted strand transfer reaction, whereby both ends retroviral DNA are inserted into host cell chromosome. Herein we present two crystal structures containing N-terminal and catalytic core domains maedi-visna virus IN in complex with binding domain common lentiviral integration co-factor LEDGF. The reveal dimer-of-dimers architecture stabilized by swapping between inner pair monomers poised to execute...
Gram-negative bacteria possess specialised biogenesis machineries that facilitate the export of amyloid subunits for construction a biofilm matrix. The secretion bacterial functional requires bespoke outer-membrane protein channel through which unfolded substrates are translocated. Here, we combine X-ray crystallography, native mass spectrometry, single-channel electrical recording, molecular simulations and circular dichroism measurements to provide high-resolution structural insight into...
Many bacterial pathogens secrete virulence (effector) proteins that interfere with immune signaling in their host. SpvD is a Salmonella enterica effector protein we previously demonstrated to negatively regulate the NF-κB pathway and promote of S. serovar Typhimurium mice. To shed light on mechanistic basis for these observations, determined crystal structure show it adopts papain-like fold characteristic cysteine-histidine-aspartate catalytic triad comprising Cys-73, His-162, Asp-182....
A library of thiazoles and selenothiazoles were synthesized via Ir-catalyzed ylide insertion chemistry. This process is a functional group, particularly heterocycle-substituent tolerant. was applied to the synthesis fanetizole, an anti-inflammatory drug, thiazole-containing drug fragment that binds peptidyl-tRNA hydrolase (Pth) in Neisseria gonorrheae bacteria.
On the basis of a series lactam and phthalimide derivatives that inhibit HIV-1 integrase, we developed new molecule, XZ-259, with biochemical antiviral activities comparable to raltegravir. We determined crystal structures XZ-259 four other in complex prototype foamy virus intasome. The compounds bind at integrase-Mg2+-DNA interface integrase active site. In assays, inhibits raltegravir-resistant integrases harboring Y143R mutation. Molecular modeling is also presented suggesting can...
Abstract The pro-inflammatory mediator leukotriene B 4 (LTB ) is implicated in the pathologies of an array diseases and thus represents attractive therapeutic target. enzyme A hydrolase (LTA H) catalyses distal step LTB synthesis hence inhibitors this have been actively pursued. Despite potent LTA H entering clinical trials all failed to show efficacy. We recently identified a secondary anti-inflammatory role for degrading neutrophil chemoattractant Pro-Gly-Pro (PGP) rationalized that...
Abstract The Neisseriaceae family of bacteria causes a range diseases including meningitis, septicaemia, gonorrhoea and endocarditis, extracts haem from haemoglobin as an important iron source within the iron-limited environment its human host. Herein we report crystal structures apo- haemoglobin-bound HpuA, essential component this import system. interface involves long loops on bacterial receptor that present hydrophobic side chains for packing against surface haemoglobin. Interestingly,...