Allosteric Model of Maraviroc Binding to CC Chemokine Receptor 5 (CCR5)
Allosteric Model of Maraviroc Binding to CC Chemokine Receptor 5 (CCR5)
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DOI：
10.1074/jbc.m111.279596
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发表时间：
2011-09-23
影响因子：
4.8
通讯作者：
Kellenberger, Esther
中科院分区：
文献类型：
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作者：
Garcia-Perez, Javier;Rueda, Patricia;Kellenberger, Esther
Maraviroc 是一种非肽类小分子人类免疫缺陷病毒 1 型 (HIV-1) 进入抑制剂，刚刚进入治疗患者的治疗库。我们最近证明，马拉韦罗与 HIV-1 辅助受体 CC 趋化因子受体 5 (CCR5) 结合，可通过变构机制阻止其与趋化因子 CCL3 和病毒包膜糖蛋白 gp120 结合。然而，对配体结合位点的不完全了解以及 CCR5 晶体结构的缺乏阻碍了对该抑制剂如何发挥作用的深入分子理解。在这里，我们通过将定点突变（SDM）与同源建模和对接相结合来解决这些问题。比较了 G 蛋白偶联受体的六种晶体结构是否适合 CCR5 建模。所有 CCR5 模型都具有同样良好的几何结构，但根据最近报道的与肽 CVX15（蛋白质数据库代码 3OE0）结合的另一个 HIV-1 辅助受体 CXCR4 的二聚体结构构建的模型与 SDM 数据最一致，并在虚拟筛选方法中将 CCR5 与非 CCR5 结合物区分开来。 SDM 和自动对接预测马拉韦罗深入插入 CCR5 跨膜腔，在那里它可以占据三个不同的结合位点，而 CCL3 和 gp120 位于 CCR5 细胞外环 2 的不同但重叠的区域。数据表明马拉韦罗在 CCL3 结合和 gp120 结合的 CCR5 中仍然可以进入跨膜腔，这有助于解释我们之前的研究 观察到该抑制剂增强了预先形成的配体-CCR5 复合物的解离。最后，我们鉴定了预测的 CCR5 二聚体界面中对 gp120 结合必需的残基，这表明受体二聚化可能代表新 CCR5 进入抑制剂的靶点。
Maraviroc is a nonpeptidic small molecule human immunodeficiency virus type 1 (HIV-1) entry inhibitor that has just entered the therapeutic arsenal for the treatment of patients. We recently demonstrated that maraviroc binding to the HIV-1 coreceptor, CC chemokine receptor 5 (CCR5), prevents it from binding the chemokine CCL3 and the viral envelope glycoprotein gp120 by an allosteric mechanism. However, incomplete knowledge of ligand-binding sites and the lack of CCR5 crystal structures have hampered an in-depth molecular understanding of how the inhibitor works. Here, we addressed these issues by combining site-directed mutagenesis (SDM) with homology modeling and docking. Six crystal structures of G-protein-coupled receptors were compared for their suitability for CCR5 modeling. All CCR5 models had equally good geometry, but that built from the recently reported dimeric structure of the other HIV-1 coreceptor CXCR4 bound to the peptide CVX15 (Protein Data Bank code 3OE0) best agreed with the SDM data and discriminated CCR5 from non-CCR5 binders in a virtual screening approach. SDM and automated docking predicted that maraviroc inserts deeply in CCR5 transmembrane cavity where it can occupy three different binding sites, whereas CCL3 and gp120 lie on distinct yet overlapped regions of the CCR5 extracellular loop 2. Data suggesting that the transmembrane cavity remains accessible for maraviroc in CCL3-bound and gp120-bound CCR5 help explain our previous observation that the inhibitor enhances dissociation of preformed ligand-CCR5 complexes. Finally, we identified residues in the predicted CCR5 dimer interface that are mandatory for gp120 binding, suggesting that receptor dimerization might represent a target for new CCR5 entry inhibitors.