Liao Chenyi, Remington Jacob M, May Victor, Li Jianing
Department of Chemistry, University of Vermont, Burlington, VT, United States.
State Key Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Dalian, China.
Front Mol Biosci. 2021 Mar 25;8:644644. doi: 10.3389/fmolb.2021.644644. eCollection 2021.
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.
相关神经肽垂体腺苷酸环化酶激活肽（PACAP）和血管活性肠肽（VIP）及其共同的PAC1、VPAC1和VPAC2受体，调节中枢和外周神经系统中的一系列生理活动。然而，缺乏比较性和分子机制研究阻碍了对它们偏好的结合选择性和功能的进一步理解。PACAP和VIP在VPAC1和VPAC2受体上具有相当的亲和力，但PACAP在PAC1受体上的效力比VIP高400 - 1000倍。为了合理设计选择性配体，非常需要从分子层面了解不同的神经肽 - 受体相互作用以及导致受体激活的受体转变背后的细节。为此，我们结合了结构信息和先进的模拟技术，来研究PACAP/VIP的结合选择性、PACAP/VIP受体变体和亚型的全长受体构象集合及转变，以及正构结合口袋中的一些关键相互作用。我们的结果揭示了对PAC1、VPAC1和VPAC2受体配体选择性很重要的不同肽 - 受体相互作用（在原子细节层面）。通过微秒级的分子动力学模拟和马尔可夫状态模型，我们还确定了每个受体不同的受体构象集合和微观状态转变路径、受体开放和关闭状态的潜在机制，以及跨膜正构口袋中受体激活的相互作用和动力学。这些分析揭示了B类G蛋白偶联受体结构 - 动力学 - 功能关系中的重要特征，为基于结构的药物发现提供了新的见解。
