Molecular simulations reveal intricate coupling between agonist-bound R-adrenergic receptors and G protein

作     者：Han, Yanxiao Dawson, John R. D. Demarco, Kevin R. Rouen, Kyle C. Ngo, Khoa Bekker, Slava Yarov-Yarovoy, Vladimir Clancy, Colleen E. Xiang, Yang K. Ahn, Surl-Hee Vorobyov, Igor 

作者机构：Univ Calif Davis Dept Physiol & Membrane Biol Davis CA 95616 USA Univ Calif Davis Biophys Grad Grp Davis CA 95616 USA Amer River Coll Sacramento CA 95841 USA Univ Calif Davis Dept Anesthesiol & Pain Med Davis CA 95616 USA Univ Calif Davis Ctr Precis Med & Data Sci Davis CA 95616 USA Univ Calif Davis Dept Pharmacol Davis CA 95616 USA VA Northern Calif Hlth Care Syst Mather CA 95655 USA Univ Calif Davis Dept Chem Engn Davis CA 95616 USA 

出 版 物：《ISCIENCE》 (iScience)

年 卷 期：2025年第28卷第2期

页      面：111741页

核心收录：

基　　金：American Heart Association Postdoctoral Fellowship National Institutes of Health Common Fund National Heart, Lung, and Blood Institute (NHLBI) [R01HL152681, U01HL126273] NHLBI [R01HL162825, R01HL147263, I01BX005100, IK6BX005753, F31HL174025] American Heart Association Predoctoral Fellowship [16PRE27260295] American Heart Association Career Development Award [19CDA34770101] National Science Foundation UC Davis Department of Physiology and Membrane Biology Research Partnership Fund UC Davis T32 Predoctoral Training in Pharmacological Sciences fellowship National Institutes of Health [T32GM099608, T32GM136597] NIGMS Institutional Training UC Davis Chemical Biology Program fellowship UC Davis T32 Predoctoral Training in Basic and Translational Cardiovascular Medicine fellowship NHLBI Institutional Training [T32HL086350] University of California Davis Department of Chemical Engineering start-up funds Extreme Science and Engineering Discovery Environment (XSEDE) [MCB170095] National Center for Super-computing Applications (NCSA) Texas Advanced Computing Center (TACC) Leadership Resource and Pathways Allocations [MCB20010] Oracle cloud credits award and Oracle for Research fellowship Pittsburgh Supercomputing Center (PSC) Anton 2 allocations [PSCA17085P, MCB160089P, PSCA18077P, PSCA16108P] 24POST1187017 OT2OD026580 R01HL174001 R01HL128537 R01GM116961 

主　　题：Protein structure aspects Computational bioinformatics 

摘      要：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 (Gs) interactions with R-adrenergic receptors (RARs), crucial GPCRs for heart function regulation and major drug targets. Our analysis revealed distinct binding behaviors of NE within R1AR and R2AR despite identical orthosteric binding pockets. R2AR had an additional binding site, explaining variations in NE binding affinities. Simulations showed significant differences in NE dissociation pathways and receptor interactions with the Gs. R1AR binds Gs more strongly, while R2AR induces greater conformational changes in the a subunit of Gs. Furthermore, GTP and GDP binding to Gs may disrupt coupling between NE and RAR, as well as between RAR and Gs. These findings may aid in designing precise RAR-targeted drugs.