Identification of distinct, ligand‐specific structural changes in a G protein‐coupled receptor

TL;DRAbstract

G protein‐coupled receptors (GPCRs) represent by far the largest class of cell surface receptors. The conformational changes in GPCR structure induced by GPCR ligands (agonists, neutral antagonists, or inverse agonists) are not well understood at present. In this study, we employed an in situ disulfide cross‐linking strategy to monitor ligand‐induced conformational changes in a series of cysteine (Cys)‐substituted mutant M3 muscarinic acetylcholine receptors. We demonstrated that muscarinic agonists inhibited disulfide cross‐linking in the A91C/T549C and F92C/F550C double Cys mutant M3 receptors. In striking contrast, inverse muscarinic agonists enhanced disulfide bond formation in the same receptor constructs. Given the predicted localization of the Cys residues present in these mutant receptors, our data strongly suggest that muscarinic agonists trigger a separation of the N‐terminal segment of the cytoplasmic tail from the cytoplasmic end of transmembrane domain I (TM I), whereas in

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