G-protein-coupled receptor allosterism: the promise and the problem(s)

2004 ◽  
Vol 32 (5) ◽  
pp. 873-877 ◽  
Author(s):  
A. Christopoulos ◽  
L.T. May ◽  
V.A. Avlani ◽  
P.M. Sexton
Keyword(s):  
G Protein ◽  
Binding Sites ◽  
G Protein Coupled Receptors ◽  
Receptor Activity ◽  
Screening Methods ◽  
Receptor Subtype ◽  
Allosteric Modulators ◽  
Physiological Regulation ◽  
Subtype Selectivity ◽  
G Protein Coupled

Allosteric modulators of G-protein-coupled receptors interact with binding sites that are topographically distinct from the orthosteric site recognized by the receptor's endogenous agonist. Allosteric ligands offer a number of advantages over orthosteric drugs, including the potential for greater receptor subtype selectivity and a more ‘physiological’ regulation of receptor activity. However, the manifestations of allosterism at G-protein-coupled receptors are quite varied, and significant challenges remain for the optimization of screening methods to ensure the routine detection and validation of allosteric ligands.

scholarly journals GRKs as Modulators of Neurotransmitter Receptors

Cells ◽  
2020 ◽  
Vol 10 (1) ◽  
pp. 52
Author(s):  
Eugenia V. Gurevich ◽  
Vsevolod V. Gurevich
Keyword(s):  
G Protein ◽  
General Model ◽  
G Protein Coupled Receptors ◽  
Receptor Internalization ◽  
Neurotransmitter Receptors ◽  
Receptor Subtype ◽  
Receptor Subtypes ◽  
Receptor Kinase ◽  
G Protein Coupled ◽  
Homologous Desensitization

Many receptors for neurotransmitters, such as dopamine, norepinephrine, acetylcholine, and neuropeptides, belong to the superfamily of G protein-coupled receptors (GPCRs). A general model posits that GPCRs undergo two-step homologous desensitization: the active receptor is phosphorylated by kinases of the G protein-coupled receptor kinase (GRK) family, whereupon arrestin proteins specifically bind active phosphorylated receptors, shutting down G protein-mediated signaling, facilitating receptor internalization, and initiating distinct signaling pathways via arrestin-based scaffolding. Here, we review the mechanisms of GRK-dependent regulation of neurotransmitter receptors, focusing on the diverse modes of GRK-mediated phosphorylation of receptor subtypes. The immediate signaling consequences of GRK-mediated receptor phosphorylation, such as arrestin recruitment, desensitization, and internalization/resensitization, are equally diverse, depending not only on the receptor subtype but also on phosphorylation by GRKs of select receptor residues. We discuss the signaling outcome as well as the biological and behavioral consequences of the GRK-dependent phosphorylation of neurotransmitter receptors where known.

scholarly journals The molecular basis of subtype selectivity of human kinin G-protein-coupled receptors

2018 ◽  
Vol 14 (3) ◽  
pp. 284-290 ◽  
Author(s):  
Lisa Joedicke ◽  
Jiafei Mao ◽  
Georg Kuenze ◽  
Christoph Reinhart ◽  
Tejaswi Kalavacherla ◽  
...  
Keyword(s):  
G Protein ◽  
Molecular Basis ◽  
G Protein Coupled Receptors ◽  
Subtype Selectivity ◽  
G Protein Coupled

scholarly journals Accelerated structure-based design of chemically diverse allosteric modulators of a muscarinic G protein-coupled receptor

2016 ◽  
Vol 113 (38) ◽  
pp. E5675-E5684 ◽  
Author(s):  
Yinglong Miao ◽  
Dahlia Anne Goldfeld ◽  
Ee Von Moo ◽  
Patrick M. Sexton ◽  
Arthur Christopoulos ◽  
...  
Keyword(s):  
G Protein ◽  
Experimental Testing ◽  
Muscarinic Acetylcholine Receptor ◽  
Enrichment Factors ◽  
Dissociation Rate ◽  
Allosteric Modulators ◽  
New Paradigm ◽  
Subtype Selectivity ◽  
Competition Binding ◽  
G Protein Coupled

Design of ligands that provide receptor selectivity has emerged as a new paradigm for drug discovery of G protein-coupled receptors, and may, for certain families of receptors, only be achieved via identification of chemically diverse allosteric modulators. Here, the extracellular vestibule of the M2 muscarinic acetylcholine receptor (mAChR) is targeted for structure-based design of allosteric modulators. Accelerated molecular dynamics (aMD) simulations were performed to construct structural ensembles that account for the receptor flexibility. Compounds obtained from the National Cancer Institute (NCI) were docked to the receptor ensembles. Retrospective docking of known ligands showed that combining aMD simulations with Glide induced fit docking (IFD) provided much-improved enrichment factors, compared with the Glide virtual screening workflow. Glide IFD was thus applied in receptor ensemble docking, and 38 top-ranked NCI compounds were selected for experimental testing. In [3H]N-methylscopolamine radioligand dissociation assays, approximately half of the 38 lead compounds altered the radioligand dissociation rate, a hallmark of allosteric behavior. In further competition binding experiments, we identified 12 compounds with affinity of ≤30 μM. With final functional experiments on six selected compounds, we confirmed four of them as new negative allosteric modulators (NAMs) and one as positive allosteric modulator of agonist-mediated response at the M2 mAChR. Two of the NAMs showed subtype selectivity without significant effect at the M1 and M3 mAChRs. This study demonstrates an unprecedented successful structure-based approach to identify chemically diverse and selective GPCR allosteric modulators with outstanding potential for further structure-activity relationship studies.

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