Université Côte d'Azur, CNRS , Institut de Chimie de Nice UMR7272 , Nice 06108 , France.
Department of Brain and Cognitive Sciences , Daegu Gyeongbuk Institute of Science and Technology , Daegu 711-873 , South Korea.
J Chem Inf Model. 2019 Jun 24;59(6):2871-2878. doi: 10.1021/acs.jcim.9b00045. Epub 2019 May 3.
Positive allosteric modulators (PAMs) of metabotropic glutamate receptor type 5 (mGluR), a prototypical class C G protein-coupled receptor (GPCR), have shown therapeutic potential for various neurological disorders. Understanding the allosteric activation mechanism is essential for the rational design of mGluR PAMs. We studied the actions of positive and negative allosteric modulators within the transmembrane domain of mGluR, using enhance-sampling all-atom molecular dynamics simulations. We found dual binding modes of the PAM, associated with distinct shapes of the allosteric pocket. The negative allosteric modulators, in contrast, showed only one binding mode. The simulations revealed the mechanism by which the PAM activated the receptor, in the absence of the orthosteric agonist (the so-called allosteric agonism). The mechanism relied on dynamic communications between amino-acid motifs that are highly conserved across class C GPCRs. The findings may guide structure-based design and virtual screening of allosteric modulators for mGluR as well as for other class C GPCRs.
代谢型谷氨酸受体 5（mGluR）的正变构调节剂（PAMs）是典型的 C 类 G 蛋白偶联受体（GPCR），已显示出在各种神经疾病中的治疗潜力。理解变构激活机制对于 mGluR PAMs 的合理设计至关重要。我们使用增强采样全原子分子动力学模拟研究了 mGluR 跨膜域内正变构调节剂和负变构调节剂的作用。我们发现 PAM 存在两种结合模式，与变构口袋的不同形状相关联。相比之下，负变构调节剂仅显示出一种结合模式。模拟揭示了在没有正构激动剂（所谓的变构激动作用）的情况下 PAM 激活受体的机制。该机制依赖于高度保守的跨 C 类 GPCR 的氨基酸基序之间的动态通讯。这些发现可能为 mGluR 以及其他 C 类 GPCR 的变构调节剂的基于结构的设计和虚拟筛选提供指导。
