Söldner Christian A, Horn Anselm H C, Sticht Heinrich
Bioinformatik, Institut für Biochemie, Emil-Fischer-Centrum, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), , Fahrstraße 17, 91054, Erlangen, Germany.
J Mol Model. 2018 Nov 29;24(12):346. doi: 10.1007/s00894-018-3873-7.
Binding of histamine to the G-protein coupled histamine H receptor plays an important role in the context of allergic reactions; however, no crystal structure of the resulting complex is available yet. To deduce the histamine binding site, we performed unbiased molecular dynamics (MD) simulations on a microsecond time scale, which allowed to monitor one binding event, in which particularly the residues of the extracellular loop 2 were involved in the initial recognition process. The final histamine binding pose in the orthosteric pocket is characterized by interactions with Asp107, Tyr108, Thr194, Asn198, Trp428, Tyr431, Phe432, and Phe435, which is in agreement with existing mutational data. The conformational stability of the obtained complex structure was subsequently confirmed in 2 μs equilibrium MD simulations, and a metadynamics simulation proved that the detected binding site represents an energy minimum. A complementary investigation of a D107A mutant, which has experimentally been shown to abolish ligand binding, revealed that this exchange results in a significantly weaker interaction and enhanced ligand dynamics. This finding underlines the importance of the electrostatic interaction between the histamine ammonium group and the side chain of Asp107 for histamine binding.
组胺与G蛋白偶联组胺H受体的结合在过敏反应中起着重要作用；然而，目前尚未获得由此形成的复合物的晶体结构。为了推断组胺结合位点，我们在微秒时间尺度上进行了无偏分子动力学（MD）模拟，该模拟能够监测一次结合事件，其中细胞外环2的残基特别参与了初始识别过程。在正构口袋中的最终组胺结合姿势的特征是与Asp107、Tyr108、Thr194、Asn198、Trp428、Tyr431、Phe432和Phe435相互作用，这与现有的突变数据一致。随后在2微秒的平衡MD模拟中证实了所获得的复合物结构的构象稳定性，元动力学模拟证明检测到的结合位点代表能量最小值。对实验表明可消除配体结合的D107A突变体的补充研究表明，这种交换导致相互作用显著减弱且配体动力学增强。这一发现强调了组胺铵基团与Asp107侧链之间的静电相互作用对组胺结合的重要性。
