Laboratory of Computational Chemistry and Biochemistry, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
J Mol Biol. 2010 Apr 16;397(5):1339-49. doi: 10.1016/j.jmb.2010.01.060. Epub 2010 Feb 2.
The mechanism of signal transduction in G-protein-coupled receptors (GPCRs) is a crucial step in cell signaling. However, the molecular details of this process are still largely undetermined. Carrying out submicrosecond molecular dynamics simulations of beta-adrenergic receptors, we found that cooperation between a number of highly conserved residues is crucial to alter the equilibrium between the active state and the inactive state of diffusible ligand GPCRs. In particular, "ionic-lock" formation in beta-adrenergic receptors is directly correlated with the protonation state of a highly conserved aspartic acid residue [Asp(2.50)] even though the two sites are located more than 20 A away from each other. Internal polar residues, acting as local microswitches, cooperate to propagate the signal from Asp(2.50) to the G-protein interaction site at the helix III-helix VI interface. Evolutionarily conserved differences between opsin and non-opsin GPCRs in the surrounding of Asp(2.50) influence the acidity of this residue and can thus help in rationalizing the differences in constitutive activity of class A GPCRs.
G 蛋白偶联受体（GPCRs）中的信号转导机制是细胞信号传递的关键步骤。然而，这一过程的分子细节在很大程度上仍未确定。通过对β-肾上腺素能受体进行亚微秒分子动力学模拟，我们发现许多高度保守残基之间的合作对于改变可扩散配体 GPCRs 的活性状态和非活性状态之间的平衡至关重要。特别是，β-肾上腺素能受体中的“离子锁”形成与高度保守的天冬氨酸残基 [Asp（2.50）] 的质子化状态直接相关，尽管这两个位点彼此之间相隔超过 20埃。作为局部微开关的内部极性残基相互协作，将信号从 Asp（2.50）传递到螺旋 III-螺旋 VI 界面的 G 蛋白相互作用位点。在围绕 Asp（2.50）的视蛋白和非视蛋白 GPCR 之间的进化保守差异影响了该残基的酸度，从而有助于解释 A 类 GPCR 组成活性的差异。
