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Publication Abstract from PubMed

G-protein-coupled receptors (GPCRs) receive signals from ligands with different efficacies, and transduce to heterotrimeric G-proteins to generate different degrees of physiological responses. Previous studies revealed how ligands with different efficacies activate GPCRs. Here, we investigate how a GPCR activates G-proteins upon binding ligands with different efficacies. We report the cryo-EM structures of beta1-adrenergic receptor (beta1-AR) in complex with Gs (GalphasGbeta1Ggamma2) and a partial agonist or a very weak partial agonist, and compare them to the beta1-AR-Gs structure in complex with a full agonist. Analyses reveal similar overall complex architecture, with local conformational differences. Cellular functional studies with mutations of beta1-AR residues show effects on the cellular signaling from beta1-AR to the cAMP response initiated by the three different ligands, with residue-specific functional differences. Biochemical investigations uncover that the intermediate state complex comprising beta1-AR and nucleotide-free Gs is more stable when binding a full agonist than a partial agonist. Molecular dynamics simulations support the local conformational flexibilities and different stabilities among the three complexes. These data provide insights into the ligand efficacy in the activation of GPCRs and G-proteins.

Structures of beta1-adrenergic receptor in complex with Gs and ligands of different efficacies.,Su M, Paknejad N, Zhu L, Wang J, Do HN, Miao Y, Liu W, Hite RK, Huang XY Nat Commun. 2022 Jul 14;13(1):4095. doi: 10.1038/s41467-022-31823-1. PMID:35835792^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.