Structural Basis for Allosteric Modulation of Class B G Protein-Coupled Receptors

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 natu...

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Bibliographic Details
Published in:Annual review of pharmacology and toxicology 2020-01, Vol.60 (1), p.89-107
Main Authors: Wootten, Denise, Miller, Laurence J
Format: Article
Language:English
Subjects:
allosteric modulation
Allosteric Regulation - drug effects
Allosteric Site
biased agonism
Drug Development
GPCRs
Humans
Ligands
RAMPs
Receptors, G-Protein-Coupled - agonists
Receptors, G-Protein-Coupled - chemistry
Receptors, G-Protein-Coupled - metabolism
structure function
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Summary: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.
ISSN:0362-1642
1545-4304
DOI:10.1146/annurev-pharmtox-010919-023301