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
Department of Physiology and Membrane Biology, University of California, Davis, Davis, CA 95616, USA.
Biophysics Graduate Group, University of California, Davis, Davis, CA 95616, USA.
iScience. 2025 Jan 2;28(2):111741. doi: 10.1016/j.isci.2024.111741. eCollection 2025 Feb 21.
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.
G蛋白偶联受体（GPCRs）和G蛋白可将激素和神经递质的信号传递穿过细胞膜，启动下游信号传导并调节细胞行为。利用先进的计算机建模和模拟，我们确定了去甲肾上腺素（NE）和刺激性G蛋白（Gs）与β-肾上腺素能受体（βARs）相互作用的原子水平结构、动力学和能量机制，βARs是调节心脏功能的关键GPCRs，也是主要的药物靶点。我们的分析揭示了尽管β1AR和β2AR具有相同的正构结合口袋，但NE在其中的结合行为却不同。β2AR有一个额外的结合位点，这解释了NE结合亲和力的差异。模拟显示NE解离途径以及受体与Gs的相互作用存在显著差异。β1AR与Gs结合更强，而β2AR在Gs的α亚基中诱导更大的构象变化。此外，GTP和GDP与Gs的结合可能会破坏NE与βAR之间以及β2AR与Gs之间的偶联。这些发现可能有助于设计精确的βAR靶向药物。
