Department of Pharmaceutical Chemistry, Philipps-University Marburg, Germany.
FEBS J. 2021 Apr;288(8):2461-2489. doi: 10.1111/febs.15841.
G protein-coupled receptors (GPCRs) play critical roles in the regulation of human physiology in response to a wide array of different extracellular stimuli and thus represent one of the largest groups of therapeutic drug targets. Recent advances in the structural characterization of GPCRs in different conformations and in complex with G proteins and arrestins have provided important insights into the mechanism and function of GPCRs. However, in order to truly understand the molecular basis of the functional versatility of GPCRs, the structural snapshots obtained by X-ray crystallography or cryo-EM need to be complimented with information about the conformational dynamics of receptors and their signaling complexes. In the last decade, a combination of biophysical approaches and computational studies has been utilized to examine the molecular motions of GPCRs and their transducer complexes and how they are regulated by ligands of different efficacy and bias. These studies revealed that GPCRs are highly dynamic allosteric proteins that can sample multiple conformational states. Ligands with distinct signaling profiles not only impact the conformational landscape of GPCRs but also of the receptor-engaged G proteins and arrestins. The conformational dynamics of GPCRs and their signaling complexes and the ligand-dependent bias sampling of distinct functional states are important underlying principles behind the complex signaling behavior of GPCRs.
G 蛋白偶联受体（GPCRs）在人类生理学的调节中起着至关重要的作用，它们能够响应广泛的不同细胞外刺激，因此是最大的治疗药物靶点之一。近年来，GPCRs 在不同构象以及与 G 蛋白和阻滞蛋白复合物中的结构特征方面的研究进展，为 GPCRs 的作用机制和功能提供了重要的见解。然而，为了真正理解 GPCRs 功能多样性的分子基础，需要将 X 射线晶体学或 cryo-EM 获得的结构静态快照与关于受体及其信号转导复合物的构象动力学的信息结合起来。在过去的十年中，已经结合了生物物理方法和计算研究，以研究 GPCR 及其转导复合物的分子运动，以及它们如何被不同效力和偏向配体所调控。这些研究表明，GPCR 是高度动态的变构蛋白，可以采样多种构象状态。具有不同信号特征的配体不仅影响 GPCR 的构象景观，也影响与受体结合的 G 蛋白和阻滞蛋白。GPCR 及其信号转导复合物的构象动力学以及配体依赖性偏向不同功能状态的采样，是 GPCR 复杂信号转导行为的重要基础原理。
