Bond PJ

Structure mapping of dengue and Zika viruses reveals functional long-range interactions

Published date : 29 Mar 2019

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.

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Journal Paper
journal
Nature Communications, 2019 Mar 29;10(1):1408. doi: 10.1038/s41467-019-09391-8
Impact Factor
12.353

Insights into water accessible pathways and the inactivation mechanism of proton translocation by the membrane-embedded domain of V-type ATPases

Published date : 01 Mar 2019

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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Journal Paper
journal
Biochimica et Biophysica Acta (BBA) - Biomembranes, Vol. 1861, Issue 5, 1 May 2019, Pg 1004-1010, doi: 10.1016/j.bbamem.2019.02.010
Impact Factor
3.438

The disordered plant dehydrin Lti30 protects the membrane during water-related stress by cross-linking lipids

Published date : 28 Feb 2019

Dehydrins are intrinsically disordered proteins, generally expressed in plants as a response to embryogenesis and water-related stress. Their suggested functions are in membrane stabilization and cell protection. All dehydrins contain at least one copy of the highly conserved K-segment, proposed to be a membrane binding motif. The dehydrin Lti30 (Arabidopsis thaliana) is upregulated during cold and drought stress conditions and comprises six K-segments, each with two adjacent histidines. Lti30 interacts with the membrane electrostatically via pH dependent protonation of the histidines.

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Journal Paper
journal
Journal of Biological Chemistry, 28 Feb 2019, doi: 10.1074/jbc.RA118.007163
Impact Factor
4.011

Infectivity of Dengue Virus Serotypes 1 and 2 Is Correlated with E-Protein Intrinsic Dynamics but Not to Envelope Conformations

Published date : 24 Jan 2019

Dengue is a mosquito-borne virus with dire health and economic impacts. Dengue is responsible for an estimated 390 million infections per year, with dengue 2 (DENV2) being the most virulent strain among the four serotypes. Interestingly, it is also in strains of this serotype that temperature-dependent large-scale morphological changes, termed “breathing,” have been observed. Although the structure of these morphologies has been solved to 3.5-Å resolution, the dynamics of the viral envelope are unknown.

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Journal Paper
journal
Structure, 27, Pg 1-13, 2019, doi: 10.1016/j.str.2018.12.006
Impact Factor
4.907

Directing GDNF-mediated neuronal signaling with proactively programmable cell-surface saccharide-free glycosaminoglycan mimetics

Published date : 04 Jan 2019

A significant barrier to harnessing the power of cell-surface glycosaminoglycans (GAGs) to modulate glial cell-line-derived neurotrophic factor (GDNF) signaling is the difficulty in accessing key GAG structures involved. Here, we report tailored GDNF signaling using synthetic polyproline-based GAG mimetics (PGMs). PGMs deliver the much needed proactive programmability for GDNF recognition and effectively modulate GDNF-mediated neuronal processes in a cellular context.

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Journal Paper
journal
Chemical Communications 2019 Jan 24;55(9):1259-1262. doi: 10.1039/c8cc09253b
Impact Factor
6.29

Energetic Fingerprinting of Ligand Binding to Paralogous Proteins: The Case of the Apoptotic Pathway

Published date : 24 Dec 2018

Networks of biological molecules are key to cellular function, governing processes ranging from signal cascade propagation to metabolic pathway regulation. Genetic duplication processes give rise to sets of regulatory proteins that have evolved from a common ancestor, leading to interactomes whose dysregulation is often associated with disease. A better understanding of the determinants of specificity at 21 interfaces shared by functionally related proteins is crucial to the rational design of novel pharmacotherapeutic agents.

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Journal Paper
journal
Journal of Chemical Inofrmation and Modeling, 2018 Dec 24. doi: 10.1021/acs.jcim.8b00765
Impact Factor
3.804

Engineering an Osmosensor by Pivotal Histidine Positioning within Disordered Helices

Published date : 29 Nov 2018

Histidine kinases (HKs) funnel diverse environmental stimuli into a single autophosphorylation event at a conserved histidine residue. The HK EnvZ is a global sensor of osmolality and cellular acid pH. In previous studies, we discovered that osmosensing in EnvZ was mediated through osmolyte-induced stabilization of the partially disordered helical backbone spanning the conserved histidine autophosphorylation site (His243).

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Journal Paper
journal
Structure, 27, 1-13, Feb 5, doi: 10.1016/j.str.2018.10.012
Impact Factor
4.907

Mechanism of Enhanced Immature Dengue Virus Attachment to Endosomal Membrane Induced by prM Antibody

Published date : 21 Nov 2018

Dengue virus (DENV) particles are released from cells in different maturation states. Fully immature DENV (immDENV) is generally non-infectious, but can become infectious when complexed with anti-precursor membrane (prM) protein antibodies. It is unknown how anti-prM antibody-coated particles can undergo membrane fusion since the prM caps the envelope (E) protein fusion loop. Here, we determined cryoelectron microscopy (cryo-EM) maps of the immDENV:anti-prM complex at different pH values, mimicking the extracellular (pH 8.0) or endosomal (pH 5.0) environments.

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Journal Paper
journal
Structure 27, 1-15, Feb 5, 2019, doi: 10.1016/j.str.2018.10.009
Impact Factor
4.907

Single-molecule studies of flavivirus envelope dynamics: Experiment and computation

Published date : 14 Sep 2018

Flaviviruses are simple enveloped viruses exhibiting complex structural and functional heterogeneities. Decades of research have provided crucial basic insights, antiviral medication and moderately successful gene therapy trials. The most infectious particle is, however, not always the most abundant one in a population, questioning the utility of classic ensemble-averaging virology approaches. Indeed, viral replication is often not particularly efficient, prone to errors or containing parallel routes.

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Journal Paper
journal
Progress in Biophysics and Molecular Biology, 2018, Sep 14, doi: 10.1016/j.pbiomolbio.2018.09.001
Impact Factor
3.427

Facile saccharide-free mimetics that recapitulate key features of glycosaminoglycan sulfation patterns

Published date : 24 Aug 2018

Controlling glycosaminoglycan (GAG) activity to exploit its immense potential in biology ultimately requires facile manipulation of sulfation patterns associated with GAGs. However, satisfying this requirement in full remains challenging, given that synthesis of GAGs is technically arduous while convenient GAG mimetics often produce sulfation patterns that are uncharacteristic of GAGs. To overcome this, we develop saccharide-free polyproline-based GAG mimetics (PGMs) that can be facilely assembled via amide coupling chemistry.

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Journal Paper
journal
Chemical Science, 2018, 9, 7940-7947, doi: 10.1039/C8SC02303D
Impact Factor
4.907