Docking and MD study of histamine H4R based on the crystal structure of H1R
Docking and MD study of histamine H4R based on the crystal structure of H1R
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基于H1R晶体结构的组胺H4R对接和MD研究
DOI：
10.1016/j.jmgm.2012.10.003
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发表时间：
2013-02-01
影响因子：
2.9
通讯作者：
Li, Youyong
中科院分区：
文献类型：
--
作者：
Feng, Zhiwei;Hou, Tingjun;Li, Youyong
组胺H4受体（Histamine H4 receptor，H4 R）是组胺受体家族的一员，属于G蛋白偶联受体（GPCRs）的A类，在组胺诱导的肥大细胞和嗜酸性粒细胞趋化性中发挥重要作用。近年来，人类组胺H1受体（H1 R）的晶体结构被报道，这对基于结构的组胺受体药物发现具有重要意义。在本工作中，首先根据H1 R的晶体结构构建H4 R和H3 R的同源模型，然后将Clobenpropit对接到H4 R的结合口袋中，可以识别两种不同的结合模式。为了选择合理的结合模式，将其他几种配体（包括激动剂和拮抗剂）对接到H4 R上，结果显示所有配体都具有一种优选的结合模式：质子化的-NH与Asp（3.32）紧密结合，咪唑-NH与Glu（5.46）相互作用。通过对H_3R和H_4R的比较，发现H_4R中的Glu（5.20）和Thr（6.55）与H_4R的选择性有关。然后，我们进行分子动力学（MD）模拟H4 R与其化合物的复杂。分子动力学结果表明，较好的对接方式更稳定。最后，我们将激动剂组胺对接到H1 R和H4 R中，然后对复合物进行20 ns的MD模拟。与组胺结合的H1 R或H4 R表现出从TM 5、TM 6和TM 7的强烈构象变化，TM 6的胞内部分向外移动，以及Tyr（7.53）的构象变化，这与最近活性GPCR的晶体结构一致。这些结果揭示了H4 R的选择性和激活机制，对开发H4 R的选择性拮抗剂和激动剂具有重要意义。(C)2012 Elsevier Inc. All rights reserved.
Histamine H4 receptor (H4R), a member of histamine receptor family, which belongs to class A of G-protein coupled receptors (GPCRs), has been reported to play a critical role in histamine-induced chemotaxis in mast cells and eosinophils. Recently, the crystal structure of human histamine H1 receptor (H1R) was reported, which facilitates structure-based drug discovery of histamine receptor significantly. In the current work, the homology models of H4R and H3R are first constructed based on the crystal structure of H1R Clobenpropit is then docked into the binding pocket of H4R and two different binding modes can be identified. In order to select a reasonable binding mode, several other ligands including agonists and antagonists are docked into H4R, and the results reveal that all ligands share one preferable binding mode: the protonated -NH tightly interacts with Asp(3.32) and the imidazole -NH interacts with Glu(5.46). By comparing H3R and H4R, we find that Glu(5.20) and Thr(6.55) in H4R involve in the selectivity of H4R. Then, we perform molecular dynamics (MD) simulations for H4R in complex with its compounds. MD results indicate that the preferable docking mode is more stable. Finally, we dock agonist histamine into H1R and H4R, and then perform 20 ns MD simulations for the complexes. H1R or H4R bound with histamine show strong conformational changes from TM5, TM6 and TM7, outward movement of intracellular part of TM6, and conformational change of Tyr(7.53), which is consistent with the recent crystal structures of active GPCRs. Our results reveal the mechanism of selectivity and activation for H4R, which is important for developing selective antagonists and agonists for H4R. (C) 2012 Elsevier Inc. All rights reserved.