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