Allosteric and Biased G Protein-Coupled Receptor Signaling Regulation: Potentials for New Therapeutics

Khoury, Étienne; Clement, Stephanie; Laporte, Stéphane A.

doi:10.3389/fendo.2014.00068

Cited by 67 publications

(51 citation statements)

References 68 publications

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“…Our results clearly demonstrate that RGS10 negatively regulates platelet functions, which may eventually yield allosteric modifiers of specific GPCR pathways in these cells [31–33]. Hence, like RGS18, RGS10, is part of a braking system that limits platelet activation downstream of G proteins.…”

Section: Discussionmentioning

confidence: 76%

RGS10 Negatively Regulates Platelet Activation and Thrombogenesis

et al. 2016

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Regulators of G protein signaling (RGS) proteins act as GTPase activating proteins to negatively regulate G protein-coupled receptor (GPCR) signaling. Although several RGS proteins including RGS2, RGS16, RGS10, and RGS18 are expressed in human and mouse platelets, the respective unique function(s) of each have not been fully delineated. RGS10 is a member of the D/R12 subfamily of RGS proteins and is expressed in microglia, macrophages, megakaryocytes, and platelets. We used a genetic approach to examine the role(s) of RGS10 in platelet activation in vitro and hemostasis and thrombosis in vivo. GPCR-induced aggregation, secretion, and integrin activation was much more pronounced in platelets from Rgs10-/- mice relative to wild type (WT). Accordingly, these mice had markedly reduced bleeding times and were more susceptible to vascular injury-associated thrombus formation than control mice. These findings suggest a unique, non-redundant role of RGS10 in modulating the hemostatic and thrombotic functions of platelets in mice. RGS10 thus represents a potential therapeutic target to control platelet activity and/or hypercoagulable states.

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Section: Discussionmentioning

confidence: 76%

RGS10 Negatively Regulates Platelet Activation and Thrombogenesis

et al. 2016

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“…In fact, dynamic allostery as a regulatory mechanism is commonly used in many biological processes (33), including, but not limited to, receptor activation in signaling (34), enzymatic catalysis (35,36) including viral maturation involving proteolysis (37), intracellular transport (38)(39)(40), and others.…”

Section: Discussionmentioning

confidence: 99%

Dynamic allostery governs cyclophilin A–HIV capsid interplay

Hou

Zhang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

153

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Host factor protein Cyclophilin A (CypA) regulates HIV-1 viral infectivity through direct interactions with the viral capsid, by an unknown mechanism. CypA can either promote or inhibit viral infection, depending on host cell type and HIV-1 capsid (CA) protein sequence. We have examined the role of conformational dynamics on the nanosecond to millisecond timescale in HIV-1 CA assemblies in the escape from CypA dependence, by magic-angle spinning (MAS) NMR and molecular dynamics (MD). Through the analysis of backbone 1H-15N and 1H-13C dipolar tensors and peak intensities from 3D MAS NMR spectra of wild-type and the A92E and G94D CypA escape mutants, we demonstrate that assembled CA is dynamic, particularly in loop regions. The CypA loop in assembled wild-type CA from two strains exhibits unprecedented mobility on the nanosecond to microsecond timescales, and the experimental NMR dipolar order parameters are in quantitative agreement with those calculated from MD trajectories. Remarkably, the CypA loop dynamics of wild-type CA HXB2 assembly is significantly attenuated upon CypA binding, and the dynamics profiles of the A92E and G94D CypA escape mutants closely resemble that of wild-type CA assembly in complex with CypA. These results suggest that CypA loop dynamics is a determining factor in HIV-1's escape from CypA dependence.

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“…We also chose to investigate selected (non-aromatic) residues that line the proximal and distal ends of ECL2, given the important role this region plays in the binding of modulators to the extracellular vestibule 18,39-41 . The results of these experiments are summarized in Supplementary Tables 2-4 and include prior mutagenesis results from our laboratory for the same set of ligands.…”

Section: Allosteric Binding and Cooperativitymentioning

confidence: 99%

Crystal structures of the M1 and M4 muscarinic acetylcholine receptors

Thal

Sun

Feng

et al. 2016

Nature

303

325

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Summary Muscarinic M1–M5 acetylcholine receptors are G protein-coupled receptors (GPCRs) that regulate many vital functions of the central and peripheral nervous systems. In particular, the M1 and M4 receptor subtypes have emerged as attractive drug targets for treatments of neurological disorders, such as Alzheimer's disease and schizophrenia, but the high conservation of the acetylcholine-binding pocket has spurred current research into targeting allosteric sites on these receptors. Here, we report the first crystal structures of the M1 and M4 muscarinic receptors bound to the inverse agonist, tiotropium. Comparison of these structures to each other, as well as the previously reported M2 and M3 receptor structures, reveals differences in the orthosteric and allosteric binding sites that contribute to a role in drug selectivity at this important receptor family. We also report identification of a cluster of residues that form a network linking the orthosteric and allosteric sites of the M4 receptor, which provides new insight into how allosteric modulation may be transmitted between the two spatially distinct domains.

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Allosteric and Biased G Protein-Coupled Receptor Signaling Regulation: Potentials for New Therapeutics

Cited by 67 publications

References 68 publications

RGS10 Negatively Regulates Platelet Activation and Thrombogenesis

RGS10 Negatively Regulates Platelet Activation and Thrombogenesis

Dynamic allostery governs cyclophilin A–HIV capsid interplay

Crystal structures of the M1 and M4 muscarinic acetylcholine receptors

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