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Conserved class B GPCR activation by a biased intracellular agonist
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Conserved class B GPCR activation by a biased intracellular agonist
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Journal Article
Conserved class B GPCR activation by a biased intracellular agonist
2023
Overview
Class B G-protein-coupled receptors (GPCRs), including glucagon-like peptide 1 receptor (GLP1R) and parathyroid hormone 1 receptor (PTH1R), are important drug targets
1
–
5
. Injectable peptide drugs targeting these receptors have been developed, but orally available small-molecule drugs remain under development
6
,
7
. Here we report the high-resolution structure of human PTH1R in complex with the stimulatory G protein (G
s
) and a small-molecule agonist, PCO371, which reveals an unexpected binding mode of PCO371 at the cytoplasmic interface of PTH1R with G
s
. The PCO371-binding site is totally different from all binding sites previously reported for small molecules or peptide ligands in GPCRs. The residues that make up the PCO371-binding pocket are conserved in class B GPCRs, and a single alteration in PTH2R and two residue alterations in GLP1R convert these receptors to respond to PCO371. Functional assays reveal that PCO371 is a G-protein-biased agonist that is defective in promoting PTH1R-mediated arrestin signalling. Together, these results uncover a distinct binding site for designing small-molecule agonists for PTH1R and possibly other members of the class B GPCRs and define a receptor conformation that is specific only for G-protein activation but not arrestin signalling. These insights should facilitate the design of distinct types of class B GPCR small-molecule agonist for various therapeutic indications.
A study reports an orally available small-molecule agonist that binds between a G protein and its receptor, and characterizes this new binding mode.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 82/80
/ 82/83
/ Agonists
/ Arrestin
/ Drugs
/ GTP-Binding Protein alpha Subunits, Gs - metabolism
/ Hormones
/ Humanities and Social Sciences
/ Humans
/ Imidazolidines - pharmacology
/ Ligands
/ Peptides
/ Proteins
/ Receptor, Parathyroid Hormone, Type 1 - agonists
/ Receptor, Parathyroid Hormone, Type 1 - classification
/ Receptor, Parathyroid Hormone, Type 1 - metabolism
/ Receptors, G-Protein-Coupled - agonists
/ Receptors, G-Protein-Coupled - classification
/ Receptors, G-Protein-Coupled - metabolism
/ Residues
/ Science
