阿片孤儿受体三维结构的比较分子模拟(英文)

目的:建立阿片孤儿受体(ORL1)的三维结构。方法:以蛙视紫红质为模板,用比较分子模拟方法进行序列联配,建立阿片孤儿受体七段跨膜区的结构;通过自己构件的数据库进行搜寻确立膜外环区的构象;对初始模型进行分子力学优化。结果:建立了阿片孤儿受体的三维结构模型;有多个氢键集中区分别存在于跨膜区和膜外环区;保守性的结合口袋位于第三、五、六、七跨膜区;预测可能的结合位点由包含Asp130、Tyr131残基的高度保守区和靠近膜外端的部分可变区组成。结论:模拟膜外环区的方法可用于其他GPCR的分子模拟;所建立的三维结构模型有助于阿片受体的结构功能研究并能为相关实验提供有益信息。

Comparative molecular modeling on 3D-structure of opioid receptor-like 1 receptor

AIM: To build the three-dimensional structure of opioid receptor-like 1 (ORL1) receptor. METHODS: Structural elements of ORL1 receptor were predicted from sequence alignments of opioid and related receptors of G protein-coupled receptor (GPCR) based on (i) the consensus, biophysical interpretations of alignment-derived properties, and (ii) tertiary structural homology to frog rhodopsin; The extracellular loops of ORL1 were built by self-constructed database searching based on geometrical constraints; initial model was refined computationally with energy minimization by molecular mechanics method. RESULTS: The calculated structure of ORL1 receptor has clusters of hydrogen bonds existing in inter-helices and extracellular loops; the ORL1 receptor has a possible ligand-binding "crevice" situated on the exlraside of the transmembrane domains between helices 3, 5, 6, and 7, which is partially covered by the extracellular loop 2 (EL-2); The binding cavity may consist of a "highly conserved region" involving the residues of Asp130, Tyr131, and an outer "conservatively variable region" containing the residues near the interface of transmembrane (TM) helices-EL loops; The molecular model obtained is qualitatively consistent with ligand affinities, hybrid peptide studies, and other experimental data. CONCLUSION: The structural model of ORL1 receptor from this study is helpful for clarifying experimental observations of ligands interacting with opioid receptors,and for designing new biological investigations.