4.7 Article

Agonist Binding and G Protein Coupling in Histamine H2 Receptor: A Molecular Dynamics Study

期刊

出版社

MDPI
DOI: 10.3390/ijms21186693

关键词

receptor-ligand interactions; G protein-coupled receptors (GPCRs); G(s)protein; ternary complex; molecular dynamics simulations; metadynamics; Gaussian accelerated simulations (GaMD); ligand binding mode; gastric acid related diseases

资金

  1. Deutsche Forschungsgemeinschaft (DFG) [GRK1910]
  2. Gauss Centre for Supercomputing e.V. [pr74su]
  3. Friedrich-Alexander-Universitat Erlangen-Nurnberg (FAU)

向作者/读者索取更多资源

The histamine H-2 receptor (H2R) plays an important role in the regulation of gastric acid secretion. Therefore, it is a main drug target for the treatment of gastroesophageal reflux or peptic ulcer disease. However, there is as of yet no 3D-structural information available hampering a mechanistic understanding of H2R. Therefore, we created a model of the histamine-H2R-G(s) complex based on the structure of the ternary complex of the beta(2)-adrenoceptor and investigated the conformational stability of this active GPCR conformation. Since the physiologically relevant motions with respect to ligand binding and conformational changes of GPCRs can only partly be assessed on the timescale of conventional MD (cMD) simulations, we also applied metadynamics and Gaussian accelerated molecular dynamics (GaMD) simulations. A multiple walker metadynamics simulation in combination with cMD was applied for the determination of the histamine binding mode. The preferential binding pose detected is in good agreement with previous data from site directed mutagenesis and provides a basis for rational ligand design. Inspection of the H2R-G(s) interface reveals a network of polar interactions that may contribute to H2R coupling selectivity. The cMD and GaMD simulations demonstrate that the active conformation is retained on a mu s-timescale in the ternary histamine-H2R-Gs complex and in a truncated complex that contains only G(s) helix alpha 5 instead of the entire G protein. In contrast, histamine alone is unable to stabilize the active conformation, which is in line with previous studies of other GPCRs.

作者

我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。

评论

主要评分

4.7
评分不足

次要评分

新颖性
-
重要性
-
科学严谨性
-
评价这篇论文

推荐

暂无数据
暂无数据