摘要：

G-protein-coupled receptors (GPCRs) mediate a wide range of cellular responses to various ligands or stimuli, and are the most important drug targets associated with human diseases. While the current advances in GPCR structural biology have greatly deepened our understanding of its activation mechanism, the highly complex changes in the structural dynamics of GPCRs during activation remain underdetermined and their links to physiological functions largely unknown. Nuclear magnetic resonance (NMR) spectroscopy is a powerful technique that allows the characterization of protein structural dynamics at atomic level, and has provided novel insights in understanding GPCR structure-function relationship. I will present our recent studies on the conformational dynamics of the M2 muscarinic acetylcholine receptor by using solution NMR technique. Our results reveal the molecular basis of how different orthosteric and allosteric ligands modulate the receptor conformational dynamics and offer new insights to facilitate drug design.

Reference

1. Xu J, Wang Q, Hübner H, Hu Y, Niu X, Wang H, Maeda S, Inoue A, Tao Y, Gmeiner P, Du Y*, Jin C*, Kobilka BK*. (2023) Structural and dynamic insights into supra-physiological activation and allosteric modulation of a muscarinic acetylcholine receptor. Nat. Commun. 14, 376
2. Xu J, Hu Y, Kaindl J, Risel P, Hübner H, Meada S, Niu X, Li H, Gmeiner P, Jin C*, Kobilka BK*. (2019) Conformational complexity and dynamics in a muscarinic receptor revealed by NMR spectroscopy. Mol. Cell. 75, 53-65