Chen Jianzhong, Wang Jian, Zeng Qingkai, Wang Wei, Sun Haibo, Wei Benzheng
School of Science, Shandong Jiaotong University, Jinan, China.
Center for Medical Artificial Intelligence, Shandong University of Traditional Chinese Medicine, Qingdao, China.
Front Mol Biosci. 2022 Aug 30;9:972463. doi: 10.3389/fmolb.2022.972463. eCollection 2022.
The adrenergic receptor (βAR), one of important members of the G protein coupled receptors (GPCRs), has been suggested as an important target for cardiac and asthma drugs. Two replicas of Gaussian accelerated molecular dynamics (GaMD) simulations are performed to explore the deactivation mechanism of the active βAR bound by three different substrates, including the agonist (P0G), antagonist (JTZ) and inverse agonist (JRZ). The simulation results indicate that the Gs protein is needed to stabilize the active state of the βAR. Without the Gs protein, the receptor could transit from the active state toward the inactive state. During the transition process, helix TM6 moves toward TM3 and TM5 in geometric space and TM5 shrinks upwards. The intermediate state is captured during the transition process of the active βAR toward the inactive one, moreover the changes in hydrophobic interaction networks between helixes TM3, TM5, and TM6 and the formation of a salt bridge between residues Arg and Glu drive the transition process. We expect that this finding can provide energetic basis and molecular mechanism for further understanding the function and target roles of the βAR.
肾上腺素能受体（βAR）是G蛋白偶联受体（GPCRs）的重要成员之一，已被认为是心脏和哮喘药物的重要靶点。进行了两次高斯加速分子动力学（GaMD）模拟，以探索与三种不同底物结合的活性βAR的失活机制，这三种底物包括激动剂（P0G）、拮抗剂（JTZ）和反向激动剂（JRZ）。模拟结果表明，Gs蛋白是稳定βAR活性状态所必需的。没有Gs蛋白，受体可能会从活性状态转变为非活性状态。在转变过程中，螺旋TM6在几何空间中向TM3和TM5移动，TM5向上收缩。在活性βAR向非活性βAR的转变过程中捕获到了中间状态，此外，螺旋TM3、TM5和TM6之间疏水相互作用网络的变化以及Arg和Glu残基之间盐桥的形成驱动了转变过程。我们期望这一发现能够为进一步理解βAR的功能和靶点作用提供能量基础和分子机制。
