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Communication over the Network of Binary Switches Regulates the Activation of A2A Adenosine Receptor

机译：二元交换机网络上的通信调节A2A腺苷受体的激活

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Dynamics and functions of G-protein coupled receptors (GPCRs) are accurately regulated by the type of ligands that bind to the orthosteric or allosteric binding sites. To glean the structural and dynamical origin of ligand-dependent modulation of GPCR activity, we performed total ~ 5 μsec molecular dynamics simulations of A2A adenosine receptor (A2AAR) in its apo, antagonist-bound, and agonist-bound forms in an explicit water and membrane environment, and examined the corresponding dynamics and correlation between the 10 key structural motifs that serve as the allosteric hotspots in intramolecular signaling network. We dubbed these 10 structural motifs “binary switches” as they display molecular interactions that switch between two distinct states. By projecting the receptor dynamics on these binary switches that yield 210 microstates, we show that (i) the receptors in apo, antagonist-bound, and agonist-bound states explore vastly different conformational space; (ii) among the three receptor states the apo state explores the broadest range of microstates; (iii) in the presence of the agonist, the active conformation is maintained through coherent couplings among the binary switches; and (iv) to be most specific, our analysis shows that W246, located deep inside the binding cleft, can serve as both an agonist sensor and actuator of ensuing intramolecular signaling for the receptor activation. Finally, our analysis of multiple trajectories generated by inserting an agonist to the apo state underscores that the transition of the receptor from inactive to active form requires the disruption of ionic-lock in the DRY motif.
机译：G蛋白偶联受体（GPCR）的动力学和功能由结合末端或颠覆结合位点的配体的类型精确调节。为了收集GPCR活性的配体依赖性调节的结构和动态起源，我们在明确的水中进行A2A腺苷受体（A2AAR）的总约为5μSEC分子动力学模拟A2A腺苷受体（A2AAR）和膜环境，并检查了作为分子内信令网络中的颠覆热点的10个关键结构基序之间的相应动态和相关性。我们称为这10个结构上的“二元开关”，因为它们显示在两个不同状态之间切换的分子相互作用。通过将受体动力学投影在这些二进制交换机上产生210微米，我们表明（i）APO中的受体，拮抗剂和激动剂束态探讨了众异的构象空间; （ii）在三个受体中，APO国家探讨了最广泛的MICROSTATE; （iii）在激动剂存在下，通过二元开关之间的相干耦合保持主动构象; （iv）是最具体的，我们的分析表明，W246位于粘合裂缝内部的深层，可以作为随后用于接受受体激活的分子内信号的激动剂传感器和致动器。最后，我们对通过将激动剂插入到APO状态下的多个轨迹的分析，使受体从无活性转变为活性形式需要在干燥基序中破坏离子锁。

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