School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China.
J Chem Inf Model. 2011 Feb 28;51(2):359-69. doi: 10.1021/ci1003448. Epub 2011 Feb 2.
The interaction between the HIV gp120 protein and coreceptor CCR5 or CXCR4 of the host cell is critical in mediating the HIV entry process. A model for the CCR5-gp120 complex has been developed. In the model, the N-terminus of CCR5 binds to three discontinuous domains of gp120, including the fourth conserved (C4) region, β19/β20 connecting loop, and V3 loop. The second extra-cellular loop (ECL2) of CCR5 also interacts with the crown part of the gp120 V3 loop. The bindings of the three CCR5 antagonists, maraviroc, aplaviroc, and vicriviroc, to the trans-membrane domain of CCR5 have been modeled. The bindings are found to affect the conformation of the ECL2 domain, which in turn drives the N-terminus of CCR5 to an altered state. Aplaviroc is more hydrophilic than maraviroc and vicriviroc, and its binding is more interfered by solvent, resulting in a quite different effect to the structure of CCR5 compared with those of the other two molecules. The above results are in accord with experimental observations and provide a structural basis for further design of CCR5 antagonists.
HIV gp120 蛋白与宿主细胞的辅助受体 CCR5 或 CXCR4 的相互作用对于介导 HIV 进入过程至关重要。已经建立了 CCR5-gp120 复合物的模型。在该模型中，CCR5 的 N 端结合到 gp120 的三个不连续结构域，包括第四保守区（C4 区）、β19/β20 连接环和 V3 环。CCR5 的第二个细胞外环（ECL2）也与 gp120 V3 环的冠部相互作用。模拟了三种 CCR5 拮抗剂马拉维若、阿普拉维若和维立西罗的结合到 CCR5 的跨膜结构域。发现这些结合会影响 ECL2 结构域的构象，进而导致 CCR5 的 N 端进入改变的状态。阿普拉维若比马拉维若和维立西罗更亲水，其结合受到溶剂的干扰更大，因此与其他两种分子相比，对 CCR5 结构的影响完全不同。上述结果与实验观察结果一致，并为进一步设计 CCR5 拮抗剂提供了结构基础。
