Allosteric Modulation of Opioid G-Protein Coupled Receptors by Sigma1 Receptors

2017 ◽  
pp. 163-175 ◽  
Author(s):  
Gavril W. Pasternak
Keyword(s):  
G Protein ◽  
Allosteric Modulation ◽  
G Protein Coupled Receptors ◽  
G Protein Coupled

ChemInform Abstract: Allosteric Modulation of G Protein-Coupled Receptors

ChemInform ◽  
2010 ◽  
Vol 32 (28) ◽  
pp. no-no
Author(s):  
Ad Ijzerman ◽  
Angeliki Kourounakis ◽  
Pieter van der Klein
Keyword(s):  
G Protein ◽  
Allosteric Modulation ◽  
G Protein Coupled Receptors ◽  
G Protein Coupled

scholarly journals Unique Features of Different Classes of G-Protein-Coupled Receptors Revealed from Sequence Coevolutionary and Structural Analysis

2021 ◽  
Author(s):  
Hung Do ◽  
Allan Haldane ◽  
Ronald Levy ◽  
Yinglong Miao
Keyword(s):  
Structural Analysis ◽  
G Protein ◽  
Allosteric Modulation ◽  
G Protein Coupled Receptors ◽  
Class A ◽  
Gpcr Activation ◽  
Residue Contacts ◽  
Critical Residue ◽  
Contact Frequency ◽  
G Protein Coupled

G-protein-coupled receptors (GPCRs) are the largest family of human membrane proteins and serve as the primary targets of about one third of currently marketed drugs. Despite the critical importance, experimental structures have been determined for only a limited portion of GPCRs. Functional mechanisms of GPCRs remain poorly understood. Here, we have constructed sequence coevolutionary models of the A, B and C classes of GPCRs and compared them with residue contact frequency maps generated with available experimental structures. Significant portions of structural residue contacts have been successfully detected in the sequence-based covariational models. "Exception" residue contacts predicted from sequence coevolutionary models but not available structures added missing links that were important for GPCR activation and allosteric modulation. Our combined coevolutionary and structural analysis revealed unique features of the different classes of GPCRs. First, we provided evidence from coevolutionary couplings that dimerization is required for activation of class C GPCRs, but not for activation of class A and B GPCRs. Second, we identified distinct residue contacts involving different sets of functional motifs for activation of the class A and B GPCRs. Finally, we uncovered critical residue contacts tuned by allosteric modulation in the three classes of GPCRs. These findings provide a promising framework for designing selective therapeutics of GPCRs.

scholarly journals Unique Features of Different Classes of G-Protein-Coupled Receptors Revealed from Sequence Coevolutionary and Structural Analysis

2021 ◽  
Author(s):  
Hung Do ◽  
Allan Haldane ◽  
Ronald M. Levy ◽  
Yinglong Miao
Keyword(s):  
G Protein ◽  
Rational Design ◽  
Allosteric Modulation ◽  
G Protein Coupled Receptors ◽  
Class A ◽  
Gpcr Activation ◽  
Residue Contacts ◽  
Critical Residue ◽  
Contact Frequency ◽  
G Protein Coupled

G-protein-coupled receptors (GPCRs) are the largest family of human membrane proteins and represent the primary targets of about one third of currently marketed drugs. Despite the critical importance, experimental structures have been determined for only a limited portion of GPCRs and functional mechanisms of GPCRs remain poorly understood. Here, we have constructed novel sequence coevolutionary models of the A and B classes of GPCRs and compared them with residue contact frequency maps generated with available experimental structures. Significant portions of structural residue contacts were successfully detected in the sequence-based covariational models. “Exception” residue contacts predicted from sequence coevolutionary models but not available structures added missing links that were important for GPCR activation and allosteric modulation. Moreover, we identified distinct residue contacts involving different sets of functional motifs for GPCR activation, such as the Na+ pocket, CWxP, DRY, PIF and NPxxY motifs in the class A and the HETx and PxxG motifs in the class B. Finally, we systematically uncovered critical residue contacts tuned by allosteric modulation in the two classes of GPCRs, including those from the activation motifs and particularly the extracellular and intracellular loops in class A GPCRs. These findings provide a promising framework for rational design of ligands to regulate GPCR activation and allosteric modulation.

scholarly journals Structural Basis for Allosteric Modulation of Class B G Protein–Coupled Receptors

2020 ◽  
Vol 60 (1) ◽  
pp. 89-107 ◽  
Author(s):  
Denise Wootten ◽  
Laurence J. Miller
Keyword(s):  
G Protein ◽  
Allosteric Modulation ◽  
G Protein Coupled Receptors ◽  
Structural Basis ◽  
Allosteric Modulators ◽  
Class B ◽  
Endogenous Proteins ◽  
And Function ◽  
Agonist Ligands ◽  
G Protein Coupled

Recent advances in our understanding of the structure and function of class B G protein–coupled receptors (GPCRs) provide multiple opportunities for targeted development of allosteric modulators. Given the pleiotropic signaling patterns emanating from these receptors in response to a variety of natural agonist ligands, modulators have the potential to sculpt the responses to meet distinct needs of different groups of patients. In this review, we provide insights into how this family of GPCRs differs from the rest of the superfamily, how orthosteric agonists bind and activate these receptors, the potential for allosteric modulators to interact with various regions of these targets, and the allosteric influence of endogenous proteins on the pharmacology of these receptors, all of which are important considerations when developing new therapies.

Allosteric Modulation of G Protein–Coupled Receptors

2007 ◽  
Vol 47 (1) ◽  
pp. 1-51 ◽  
Author(s):  
Lauren T. May ◽  
Katie Leach ◽  
Patrick M. Sexton ◽  
Arthur Christopoulos
Keyword(s):  
G Protein ◽  
Allosteric Modulation ◽  
G Protein Coupled Receptors ◽  
G Protein Coupled

Allosteric modulation of G-protein-coupled receptors

2001 ◽  
Vol 11 (12) ◽  
pp. 1889-1904 ◽  
Author(s):  
Ad P IJzerman ◽  
Ineke van Wijngaarden ◽  
Willem Soudijn
Keyword(s):  
G Protein ◽  
Allosteric Modulation ◽  
G Protein Coupled Receptors ◽  
G Protein Coupled
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