Molecular Simulations Reveal Intricate Coupling Between Agonist-bound β-adrenergic Receptors and G Protein

Overview

Journal iScience

Publisher Cell Press

Date 2025 Feb 3

PMID 39898043

Authors

Yanxiao Han

John R D Dawson

Kevin R DeMarco

Kyle C Rouen

Khoa Ngo

Slava Bekker

Vladimir Yarov-Yarovoy

Colleen E Clancy

Yang K Xiang

Surl-Hee Ahn

Igor Vorobyov

Affiliations

Soon will be listed here.

Abstract

G protein-coupled receptors (GPCRs) and G proteins transmit signals from hormones and neurotransmitters across cell membranes, initiating downstream signaling and modulating cellular behavior. Using advanced computer modeling and simulation, we identified atomistic-level structural, dynamic, and energetic mechanisms of norepinephrine (NE) and stimulatory G protein (G) interactions with β-adrenergic receptors (βARs), crucial GPCRs for heart function regulation and major drug targets. Our analysis revealed distinct binding behaviors of NE within βAR and βAR despite identical orthosteric binding pockets. βAR had an additional binding site, explaining variations in NE binding affinities. Simulations showed significant differences in NE dissociation pathways and receptor interactions with the G. βAR binds G more strongly, while βAR induces greater conformational changes in the α subunit of G. Furthermore, GTP and GDP binding to G may disrupt coupling between NE and βAR, as well as between βAR and G. These findings may aid in designing precise βAR-targeted drugs.

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