Molecular Basis of Class B GPCR Selectivity for the Neuropeptides PACAP and VIP.
Molecular Basis of Class B GPCR Selectivity for the Neuropeptides PACAP and VIP.
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DOI：
10.3389/fmolb.2021.644644
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发表时间：
2021
影响因子：
5
通讯作者：
Li J
中科院分区：
文献类型：
--
作者：
Liao C;Remington JM;May V;Li J
相关的神经肽PACAP和VIP及其共享的PAC 1、VPAC 1和VPAC 2受体调节中枢和外周神经系统中的大量生理活动。然而，缺乏比较和分子机理的研究阻碍了进一步了解他们的首选结合选择性和功能。PACAP和VIP对VPAC 1和VPAC 2受体的亲和力相当，但PACAP对PAC 1受体的效力比VIP高400- 1，000倍。不同的神经肽受体相互作用的分子理解和细节的受体转换导致受体活化是非常需要的选择性配体的合理设计。为此，我们结合了结构信息和先进的模拟技术，研究PACAP/VIP结合的选择性，全长受体构象合奏和过渡的PACAP/VIP受体的变体和亚型，和一些关键的相互作用的正构结合口袋。我们的研究结果揭示了差异肽受体相互作用（在原子的细节）重要的PAC 1，VPAC 1和VPAC 2受体配体的选择性。使用微秒长的分子动力学模拟和马尔可夫状态模型，我们还确定了不同的受体构象合奏和微观状态转换路径为每个受体，潜在的机制受体开放和关闭状态，和相互作用和动力学在跨膜正构口袋受体激活。这些分析揭示了B类GPCR结构-动力学-功能关系的重要特征，为基于结构的药物发现提供了新的见解。
The related neuropeptides PACAP and VIP, and their shared PAC1, VPAC1 and VPAC2 receptors, regulate a large array of physiological activities in the central and peripheral nervous systems. However, the lack of comparative and molecular mechanistic investigations hinder further understanding of their preferred binding selectivity and function. PACAP and VIP have comparable affinity at the VPAC1 and VPAC2 receptor, but PACAP is 400–1,000 fold more potent than VIP at the PAC1 receptor. A molecular understanding of the differing neuropeptide-receptor interactions and the details underlying the receptor transitions leading to receptor activation are much needed for the rational design of selective ligands. To these ends, we have combined structural information and advanced simulation techniques to study PACAP/VIP binding selectivity, full-length receptor conformation ensembles and transitions of the PACAP/VIP receptor variants and subtypes, and a few key interactions in the orthosteric-binding pocket. Our results reveal differential peptide-receptor interactions (at the atomistic detail) important for PAC1, VPAC1 and VPAC2 receptor ligand selectivity. Using microsecond-long molecular dynamics simulations and the Markov State Models, we have also identified diverse receptor conformational ensembles and microstate transition paths for each receptor, the potential mechanisms underlying receptor open and closed states, and the interactions and dynamics at the transmembrane orthosteric pocket for receptor activation. These analyses reveal important features in class B GPCR structure-dynamics-function relationships, which provide novel insights for structure-based drug discovery.