Huber RG

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.

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

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.

type
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.

type
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).

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

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.

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

A Funneled Conformational Landscape Governs Flavivirus Fusion Peptide Interaction with Lipid Membranes

Published date : 06 Jun 2018

During host cell infection by flaviviruses such as dengue and Zika, acidic pH within the endosome triggers a conformational change in the envelope protein on the outer surface of the virion. This results in exposure of the ∼15 residue fusion peptide (FP) region, freeing it to induce fusion between the viral and endosomal membranes. A better understanding of the conformational dynamics of the FP in the presence of membranes, and the basis for its selectivity for anionic lipid species present within the endosome, would facilitate its therapeutic targeting with antiviral drugs and antibodies.

type
Journal Paper
journal
Journal of Chemical Theory and Computation, 2018 Jul 10;14(7):3920-3932. doi: 10.1021/acs.jctc.8b00438
Impact Factor
5.399

Partial Intrinsic Disorder Governs the Dengue Capsid Protein Conformational Ensemble

Published date : 24 May 2018

The 11 kDa, positively charged dengue capsid protein (C protein) exists stably as a homodimer and co-localizes with the viral genome within mature viral particles. Its core is composed of four alpha helices encompassing a small hydrophobic patch that may interact with lipids, but approximately 20% of the protein at the N-terminus is intrinsically disordered, making it challenging to elucidate its conformational landscape.

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Journal Paper
journal
ACS Chemical Biology 2018 Jun 15;13(6):1621-1630. doi: 10.1021/acschembio.8b00231
Impact Factor
4.592

A Thermodynamic Funnel Drives Bacterial Lipopolysaccharide Transfer in the TLR4 Pathway

Published date : 17 May 2018

The Gram-negative bacterial outer membrane contains lipopolysaccharide, which potently stimulates the mammalian innate immune response. This involves a relay of specialized complexes culminating in transfer of lipopolysaccharide from CD14 to Toll-like receptor 4 (TLR4) and its co-receptor MD-2 on the cell surface, leading to activation of downstream inflammatory responses. In this study we develop computational models to trace the TLR4 cascade in near-atomic detail.

type
Journal Paper
journal
Structure, 26, Pg 1-11, July 3, 2018, doi: 10.1016/j.str.2018.04.007
Impact Factor
4.907

An Optical Technique for Mapping Microviscosity Dynamics in Cellular Organelles

Published date : 12 Apr 2018

Microscopic viscosity (microviscosity) is a key determinant of diffusion in the cell and defines the rate of biological processes occurring at the nanoscale, including enzyme-driven metabolism and protein folding. Here we establish a rotor-based organelle viscosity imaging (ROVI) methodology that enables real-time quantitative mapping of cell microviscosity. This approach uses environment-sensitive dyes termed molecular rotors, covalently linked to genetically encoded probes to provide compartment-specific microviscosity measurements via fluorescence lifetime imaging.

type
Journal Paper
journal
ACS Nano, 18 April 2018, doi: 10.1021/acsnano.8b00177
Impact Factor
13.942

Protein-protein interactions in paralogues: Electrostatics modulates specificity on a conserved steric scaffold

Published date : 17 Oct 2017

An improved knowledge of protein-protein interactions is essential for better understanding of metabolic and signaling networks, and cellular function. Progress tends to be based on structure determination and predictions using known structures, along with computational methods based on evolutionary information or detailed atomistic descriptions.

type
Journal Paper
journal
PLOS ONE, 10 Oct 2017, doi: 10.1371/journal.pone.018592
Impact Factor
2.806