Medicinal Chemistry Division, Dr. B.R. Ambedkar Center for Biomedical Research, University of Delhi, North Campus, Mall Road, Delhi, 110007, India.
Amino Acids. 2012 Oct;43(4):1451-64. doi: 10.1007/s00726-012-1218-x. Epub 2012 Jan 26.
G-protein-coupled receptors (GPCRs) are cell surface receptors. The dynamic property of receptor-receptor interactions in GPCRs modulates the kinetics of G-protein signaling and stability. In the present work, the structural and dynamic study of A(2A)R-D(2)R interactions was carried to acquire the understanding of the A(2A)R-D(2)R receptor activation and deactivation process, facilitating the design of novel drugs and therapeutic target for Parkinson's disease. The structure-based features (Alpha, Beta, SurfAlpha, and SurfBeta; GapIndex, Leakiness and Gap Volume) and slow mode model (ENM) facilitated the prediction of kinetics (K (off), K (on), and K (d)) of A(2A)R-D(2)R interactions. The results demonstrated the correlation coefficient 0.294 for K (d) and K (on) and the correlation coefficient 0.635 for K (d) and K (off), and indicated stable interfacial contacts in the formation of heterodimer. The coulombic interaction involving the C-terminal tails of the A(2A)R and intracellular loops (ICLs) of D(2)R led to the formation of interfacial contacts between A(2A)R-D(2)R. The properties of structural dynamics, ENM and KFC server-based hot-spot analysis illustrated the stoichiometry of A(2A)R-D(2)R contact interfaces as dimer. The propensity of amino acid residues involved in A(2A)R-D(2)R interaction revealed the presence of positively (R, H and K) and negatively (E and D) charged structural motif of TMs and ICL3 of A(2A)R and D(2)R at interface of dimer contact. Essentially, in silico structural and dynamic study of A(2A)R-D(2)R interactions will provide the basic understanding of the A(2A)R-D(2)R interfacial contact surface for activation and deactivation processes, and could be used as constructive model to recognize the protein-protein interactions in receptor assimilations.
G 蛋白偶联受体（GPCRs）是细胞表面受体。GPCR 中受体-受体相互作用的动态特性调节 G 蛋白信号转导和稳定性的动力学。在本工作中，进行了 A(2A)R-D(2)R 相互作用的结构和动态研究，以获得对 A(2A)R-D(2)R 受体激活和失活过程的理解，为帕金森病的新型药物和治疗靶点的设计提供了便利。基于结构的特征（Alpha、Beta、SurfAlpha、SurfBeta；GapIndex、Leakiness 和 Gap Volume）和慢模模型（ENM）有助于预测 A(2A)R-D(2)R 相互作用的动力学（K (off)、K (on) 和 K (d)）。结果表明 K (d) 和 K (on) 的相关系数为 0.294，K (d) 和 K (off) 的相关系数为 0.635，表明在异二聚体形成过程中存在稳定的界面接触。涉及 A(2A)R 的 C 末端尾巴和 D(2)R 的细胞内环（ICLs）的库仑相互作用导致 A(2A)R-D(2)R 之间形成界面接触。结构动力学、ENM 和 KFC 服务器的热点分析的性质说明了 A(2A)R-D(2)R 接触界面的化学计量作为二聚体。涉及 A(2A)R-D(2)R 相互作用的氨基酸残基的倾向表明，二聚体接触界面处 A(2A)R 和 D(2)R 的跨膜和 ICL3 存在带正电荷（R、H 和 K）和带负电荷（E 和 D）的结构模体。从本质上讲，A(2A)R-D(2)R 相互作用的计算结构和动力学研究将为 A(2A)R-D(2)R 界面接触表面的激活和失活过程提供基本的理解，并可作为识别受体吸收中蛋白质-蛋白质相互作用的建设性模型。
