CCR5 interactions with the variable 3 loop of gp120.
CCR5 interactions with the variable 3 loop of gp120.
复制标题
CCR5 与 gp120 的变量 3 环相互作用。
DOI：
10.1007/s00894-006-0117-z
复制
发表时间：
2007
影响因子：
2.2
通讯作者：
Trent,JohnO
中科院分区：
文献类型：
--
作者：
Napier,KelbyB;Wang,Zi-xuan;Peiper,StephenC;Trent,JohnO
G蛋白偶联受体CCR5在病理上是HIV-1嗜巨噬细胞(R5)毒株的主要辅助受体。负责共受体活性的相互作用尚不清楚。利用基于视紫红质的同源模型，通过显式溶剂化，对CCR5的胞外和相邻跨膜结构域进行了分子动力学模拟。通过对CCR5和gp120的可变3环的对接和分子动力学模拟，构建了辅助受体结合的功能单元，gp120的可变3环是辅助受体利用的主要决定因素。可变3环主要与CCR5的氨基末端和第二胞外环相互作用，提供了关于共同受体结合位点的新的结构信息。检测了改变趋化因子结合和共受体活性的丙氨酸突变体。分子动力学模拟在gp120可变3环和不带gp120可变3环的情况下，能够成功地使这些突变体的活性合理化，为所提出的模型提供支持。在这些结果的基础上，研究了CCR5的整体复合体gp120，包括V3环和CD4。利用计算分析，结合分子生物学数据，为理解CCR5作为HIV-1的共同受体的使用提供了强有力的方法。图CCR5的复合体，包括V3环的gp120，以及CD4的四个胞外结构域。展示了700FPS分子动力学模拟中最后50FPS的络合物的平均结构。分子显示为带状，CCR5为蓝色，V3环为红色，gp120不包括V3环为绿色，而CD4为青色。V3环4°内的CCR5残基以黄色条显示，而不包括V3环的gp120与CCR5的4°的残基以橙色带显示。
The G-protein coupled receptor CCR5 functions pathologically as the primary co-receptor for macrophage tropic (R5) strains of HIV-1. The interactions responsible for co-receptor activity are unknown. Molecular-dynamics simulations of the extracellular and adjacent transmembrane domains of CCR5 were performed with explicit solvation utilizing a rhodopsin-based homology model. The functional unit of co-receptor binding was constructed via docking and molecular-dynamics simulation of CCR5 and the variable 3 loop of gp120, which is a dominant determinant of co-receptor utilization. The variable 3 loop was demonstrated to interact primarily with the amino terminus and the second extracellular loop of CCR5, providing novel structural information regarding the co-receptor-binding site. Alanine mutants that alter chemokine binding and co-receptor activity were examined. Molecular-dynamics simulations with and without the variable 3 loop of gp120 were able to rationalize the activities of these mutants successfully, providing support for the proposed model. Based on these results, the global complex of CCR5, gp120 including the V3 loop and CD4, was investigated. The utilization of computational analysis, in combination with molecular biological data, provides a powerful approach for understanding the use of CCR5 as a co-receptor by HIV-1.FigureComplex of CCR5, gp120 including the V3 loop, and the four extracellular domains of CD4. The averaged structure of the complex over the last 50 ps of the 700 ps molecular dynamics simulation is shown. Molecules are shown as ribbons, with CCR5 in blue, the V3 loop in red, gp120 excluding the V3 loop in green, and CD4 in cyan. Residues of CCR5 within 4 Å of the V3 loop are shown in yellow ribbon, while residues of gp120 excluding the V3 loop with 4 Å of CCR5 are shown in orange ribbon.