北京大学学报(自然科学版)

CCR5膜外二硫键Cys20-Cys269对其构象完整性以及功能行使起关键作用

柳树群, 孙之荣   

  1. 清华大学生物科学与技术系,生物信息学研究所,北京,100084
  • 收稿日期:2003-11-12 出版日期:2004-07-20 发布日期:2004-07-20

The Extracellular Disulfide Bond Cys20-Cys269 of CCR5 is Important for Its Conformational Integrity Maintenance and Function Performance

LIU Shuqun, SUN Zhirong   

  1. Institue of Bioinformatics, Department of Biological sciences and Biotechnology, Tsinghua University, Beijing, 100084
  • Received:2003-11-12 Online:2004-07-20 Published:2004-07-20

摘要: 人类化学趋化因子受体CCR5是HIV-1病毒进入人体细胞的主要辅助受体。实验表明,CCR5分子的N末端区域对化学趋化因子结合以及HIV病毒入侵起关键作用。用同源模建的方法构建CCR5结构模型,并对该模型的胞外结构域进行了1ns高温分子动力学和200ps常温分子动力学模拟。结果表明,CCR5的胞外结构域整体上表现为一个包装紧密的球形构象,二硫键Cys20-Cys269对这一构象的形成以及N末端区域的空间取向起关键作用,同时,二硫键的存在使N末端1-19区域定位在胞外结构域的顶部,并增加N末端构象柔性,使其有机会伸展到胞外空间去。根据这一结果和现有的实验证据,提出了HIV-CCR5两步结合机制。

关键词: CCR5, 分子动力学模拟, N末端区域, 二硫键, HIV

Abstract: The human chemokine receptor CCR5 is a major coreceptor for human immunodeficiency virus type-1 strains entry into cell. Studies of site directed mutagenesis and chimeric receptors have indicated that the N terminus region of CCR5 is important for chemokines binding, viral fusion, and entry. Three-dimensional models of CCR5 were built by using homology modeling approach, a 1ns high temperature (1000K) molecular dynamics simulation and a subsequent 200ps normal temperature molecular dynamics simulation were performed for CCR5 extracellular domain. The results indicate that the extracellular segments of CCR5 form a well-packet globular domain, the disulfide bond Cys20-Cys269 is essential in keeping conformational integrity of extracellular domain and controlling specific orientation of N terminus region that involved in ligands and HIV binding. Also, this disulfide bond enhances the conformational flexibility of N terminus, makes it locate at the top surface of extracellular domain, and affords N terminus more opportunities to project into the outer space of this domain. Integration these results with available experimental data, a two-step gp120-CCR5 binding mechanism is proposed.

Key words: CCR5, molecular dynamics simulation, N terminus region, disulfide bond, HIV

中图分类号: