A5001674990- Lipid Membrane Structure and Behavior
- Protein Structure and Dynamics
- Mosquito-borne diseases and control
- Bacterial Genetics and Biotechnology
- Immune Response and Inflammation
- RNA and protein synthesis mechanisms
- SARS-CoV-2 and COVID-19 Research
- Bacteriophages and microbial interactions
- HIV Research and Treatment
- Antimicrobial Peptides and Activities
- ATP Synthase and ATPases Research
- Monoclonal and Polyclonal Antibodies Research
- Viral Infections and Vectors
- Influenza Virus Research Studies
- Spectroscopy and Quantum Chemical Studies
- Escherichia coli research studies
- Malaria Research and Control
- DNA and Nucleic Acid Chemistry
- Insect symbiosis and bacterial influences
- Enzyme Structure and Function
- Glycosylation and Glycoproteins Research
- Antibiotic Resistance in Bacteria
- Photosynthetic Processes and Mechanisms
- RNA modifications and cancer
- Mitochondrial Function and Pathology
Bioinformatics Institute
2016-2025
Agency for Science, Technology and Research
2016-2025
National University of Singapore
2016-2025
Korea Institute for Advanced Study
2019
University of Dundee
2019
University of Cambridge
2010-2016
Unilever (United Kingdom)
2011-2014
Max Planck Society
2009-2013
Max Planck Institute of Biophysics
2008-2010
University of Oxford
2002-2010
IRE1 couples endoplasmic reticulum unfolded protein load to RNA cleavage events that culminate in the sequence-specific splicing of Xbp1 mRNA and regulated degradation diverse membrane-bound mRNAs. We report on identification a small molecule inhibitor attains its selectivity by forming an unusually stable Schiff base with lysine 907 endonuclease domain, explained solvent inaccessibility imine bond enzyme-inhibitor complex. The (abbreviated 4μ8C) blocks substrate access active site...
Microscopic viscosity (microviscosity) is a key determinant of diffusion in the cell and defines rate biological processes occurring at nanoscale, including enzyme-driven metabolism protein folding. Here we establish rotor-based organelle imaging (ROVI) methodology that enables real-time quantitative mapping microviscosity. This approach uses environment-sensitive dyes termed molecular rotors, covalently linked to genetically encoded probes provide compartment-specific microviscosity...
Abstract There is a link between high lipopolysaccharide (LPS) levels in the blood and metabolic syndrome, syndrome predisposes patients to severe COVID-19. Here, we define an interaction SARS-CoV-2 spike (S) protein LPS, leading aggravated inflammation vitro vivo. Native gel electrophoresis demonstrated that S binds LPS. Microscale thermophoresis yielded KD of ∼47 nM for interaction. Computational modeling all-atom molecular dynamics simulations further substantiated experimental results,...
The spike (S) protein is the main handle for SARS-CoV-2 to enter host cells via surface angiotensin-converting enzyme 2 (ACE2) receptors. How ACE2 binding activates proteolysis of S unknown. Here, using amide hydrogen–deuterium exchange mass spectrometry and molecular dynamics simulations, we have mapped S:ACE2 interaction interface uncovered long-range allosteric propagation sites necessary host-mediated protein, critical viral entry. Unexpectedly, enhances at a distal S1/S2 cleavage site...
Interactions of lipids are central to the folding and stability membrane proteins. Coarse-grained molecular dynamics simulations have been used reveal mechanisms self-assembly protein/membrane protein/detergent complexes for representatives two classes protein, namely, glycophorin (a simple alpha-helical bundle) OmpA beta-barrel). The accuracy coarse-grained is established via comparison with equivalent atomistic micelles. simulation OmpA/bilayer reveals how a folded outer protein can be...
Detailed models are presented for the triple-stranded polynucleotide helices of poly(U).poly(A).poly(U) (two forms), poly(U).poly d(A).poly(U), poly d(C).poly d(I).poly d(C), d(T).poly d(A).poly d(T) and poly(I).poly(A).poly(I). The were generated using a computerized, linked-atom procedure which preserves standard bond lengths, angles sugar ring conformations, constrains to have pitches symmetries observed in X-ray diffraction experiments, optimises non-bonded interatomic contacts including...
Antimicrobial peptides are small, cationic proteins that can induce lysis of bacterial cells through interaction with their membranes. Different mechanisms for cell have been proposed, but these models tend to neglect the role chemical composition membrane, which differs between species and be heterogeneous even within a single cell. Moreover, envelope Gram-negative bacteria such as E. coli contains two membranes differing compositions. To this end, we report first molecular dynamics...
Protein cavities and tunnels are critical in determining phenomena such as ligand binding, molecular transport, enzyme catalysis. Molecular dynamics (MD) simulations enable the exploration of flexibility conformational plasticity protein cavities, extending information available from static experimental structures relevant to, for example, drug design. Here, we present a new tool (trj_cavity) implemented within GROMACS ( www.gromacs.org ) framework rapid identification characterization...
Good quality x-ray diffraction patterns have been obtained of polycrystalline fibers containing 2-hydroxyethanethiolato(2,2'2"-terpyridine)platinum(II) bound to calf thymus DNA by intercalation. The photographs strongly support the neighbor exclusion binding model in which electron-dense platinum atoms are regularly distributed at 10.2 A intervals, every other interbase pair site.
Abstract Dengue (DENV) and Zika (ZIKV) viruses are clinically important members of the Flaviviridae family with an 11 kb positive strand RNA genome that folds to enable virus function. Here, we perform structure interaction mapping on four DENV ZIKV strains inside virions in infected cells. Comparative analysis SHAPE reactivities across serotypes nominates potentially functional regions highly structured, conserved, contain low synonymous mutation rates. Interaction by SPLASH identifies many...
Centrosomes associate with spindle poles; thus, the presence of two centrosomes promotes bipolar assembly in normal cells. Cancer cells often contain supernumerary centrosomes, and to avoid multipolar mitosis cell death, these are clustered into poles by microtubule motor protein HSET. We report discovery an allosteric inhibitor HSET, CW069, which we designed using a methodology on interface chemistry biology. Using this approach, explored millions compounds silico utilized convergent...
Infection and tissue damage induces assembly of supramolecular organizing centres (SMOCs)), such as the Toll-like receptor (TLR) MyDDosome, to co-ordinate inflammatory signaling. SMOC is thought drive digital all-or-none responses, yet TLR activation by diverse microbes anything from mild severe inflammation. Using single-molecule imaging TLR4-MyDDosome signaling in living macrophages, we find that MyDDosomes assemble within minutes TLR4 stimulation. TLR4/MD2 leads only formation...
RNase E, which is the central component of multienzyme RNA degradosome, serves as a scaffold for interaction with other enzymes involved in mRNA degradation including DEAD-box helicase RhlB. Epifluorescence microscopy under live cell conditions shows that E and RhlB are membrane associated, but neither protein forms cytoskeletal-like structures reported earlier by Taghbalout Rothfield. We show association depends on direct anchored to inner cytoplasmic through an MTS (Membrane Targeting...
Bacterial microcompartments (BMCs) are nanoscale proteinaceous organelles that encapsulate enzymes from the cytoplasm using an icosahedral protein shell resembles viral capsids. Of particular interest carboxysomes (CBs), which sequester CO2-fixing ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) to enhance carbon assimilation. The carboxysome serves as a semi-permeable barrier for passage of metabolites in and out CO2 fixation. How directs influx efflux molecules effective manner...
A central tenet in the design of vaccines is display native-like antigens elicitation protective immunity. The abundance N-linked glycans across SARS-CoV-2 spike protein a potential source heterogeneity among many different vaccine candidates under investigation. Here, we investigate glycosylation recombinant proteins from five laboratories and compare them against S infectious virus, cultured Vero cells. We find patterns that are conserved all samples, this can be associated with...
Abstract Indirect somatic genetic rescue (SGR) of a germline mutation is thought to be rare in inherited Mendelian disorders. Here, we establish that acquired mutations the EIF6 gene are frequent mechanism SGR Shwachman-Diamond syndrome (SDS), leukemia predisposition disorder caused by defect ribosome assembly. Biallelic SBDS or EFL1 genes SDS impair release anti-association factor eIF6 from 60S ribosomal subunit, key step translational activation ribosomes. identify diverse mosaic events...