Bond PJ
Molecular basis of dengue virus serotype 2 morphological switch from 29°C to 37°C
The ability of DENV2 to display different morphologies (hence different antigenic properties) complicates vaccine and therapeutics development. Previous studies showed most strains of laboratory adapted DENV2 particles changed from smooth to “bumpy” surfaced morphology when the temperature is switched from 29°C at 37°C.
ReadThe structural basis for membrane assembly of immunoreceptor signalling complexes
Immunoreceptors are TM complexes that consist of separate ligand-binding and signal-transducing modules. Mounting evidence suggests that interactions with the local environment may influence the architecture of these TM domains, which assemble via crucial sets of conserved ionisable residues, and also control the peripheral association of immunoreceptor tyrosine-based activation motifs (ITAMs) whose phosphorylation triggers cytoplasmic signalling cascades. We now report a molecular dynamics (MD) simulation study of the archetypal T cell receptor (TCR) and its cluster of differentiation 3 (CD3) signalling partners, along with the analogous DNAX-activation protein of 12 kDa (DAP12)/natural killer group 2C (NKG2C) complex.
ReadMultiscale modeling of innate immune receptors: Endotoxin recognition and regulation by host defense peptides
The innate immune system provides a first line of defense against foreign microorganisms, and is typified by the Toll-like receptor (TLR) family. TLR4 is of particular interest, since over-stimulation of its pathway by excess lipopolysaccharide (LPS) molecules from the outer membranes of Gram-negative bacteria can result in sepsis, which causes millions of deaths each year. In this review, we outline our use of molecular simulation approaches to gain a better understanding of the determinants of LPS recognition, towards the search for novel immunotherapeutics.
ReadA T164S mutation in the dengue virus NS1 protein is associated with greater disease severity in mice
Dengue viruses cause severe and sudden human epidemics worldwide. The secreted form of the nonstructural protein 1 (sNS1) of dengue virus causes vascular leakage, a hallmark of severe dengue disease. Here, we reverse engineered the T164S mutation of NS1, associated with the severity of dengue epidemics in the Americas, into a dengue virus serotype 2 mildly infectious strain.
ReadMultiscale Modeling and Simulation Approaches to Lipid-Protein Interactions
Lipid membranes play a crucial role in living systems by compartmentalizing biological processes and forming a barrier between these processes and the environment. Naturally, a large apparatus of biomolecules is responsible for construction, maintenance, transport, and degradation of these lipid barriers.
ReadStructure and subunit arrangement of Mycobacterial F1FO ATP synthase and novel features of the unique mycobacterial subunit δ
In contrast to other prokaryotes, the Mycobacterial F1FO ATP synthase (α3:β3:γ:δ:ε:a:b:b':c9) is essential for growth. The mycobacterial enzyme is also unique as a result of its 111 amino acids extended δ subunit, whose gene is fused to the peripheral stalk subunit b. Recently, the crystallographic structures of the mycobacterial α3:β3:γ:ε-domain and c subunit ring were resolved. Here, we report the first purification protocol of the intact M.
ReadStructure mapping of dengue and Zika viruses reveals functional long-range interactions
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 and interaction mapping on four DENV and ZIKV strains inside virions and in infected cells. Comparative analysis of SHAPE reactivities across serotypes nominates potentially functional regions that are highly structured, conserved, and contain low synonymous mutation rates.
ReadInsights into water accessible pathways and the inactivation mechanism of proton translocation by the membrane-embedded domain of V-type ATPases
V-type ATPases are multi-protein complexes, which acidify cellular compartments in eukaryotes. They pump protons against an ion gradient, driven by a mechano-chemical framework that exploits ATP hydrolysis as an energy source. This process drives the rotation of the so-called c-ring, a membrane embedded complex in the Vo-domain of the V-type ATPase, resulting in translocation of protons across the membrane. One way in which the enzyme is regulated is by disassembly and reassembly of the V1-domain with the Vo-domain, which inactivates and reactivates the enzyme, respectively.
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