Structural and molecular interactions of CCR5 inhibitors with CCR5
Structural and molecular interactions of CCR5 inhibitors with CCR5
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CCR5 抑制剂与 CCR5 的结构和分子相互作用
DOI：
10.1074/jbc.m512688200
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发表时间：
2006-05-05
影响因子：
4.8
通讯作者：
Mitsuya, H
中科院分区：
文献类型：
--
作者：
Maeda, K;Das, D;Mitsuya, H
我们已经表征了CC-趋化因子受体5（CCR 5）与三种CCR 5抑制剂的结构和分子相互作用，所述CCR 5抑制剂对R5人类免疫缺陷病毒1型（HIV-1）具有活性，包括有效的体外和体内CCR 5抑制剂aplaviroc（AVC）。饱和结合试验和结构分析获得的数据描绘了负责CCR 5抑制剂与CCR 5结合的关键相互作用，并说明它们的结合位点位于细胞外环界面中的主要亲脂性口袋中和CCR 5的上跨膜（TM）结构域内。AVC的CCR 5结合位点的突变降低了gp 120与CCR 5的结合和对HIV-1感染的易感性，尽管也降低了gp 120结合和HIV-1感染性的TM 4和TM 5的突变对CC-趋化因子的结合的影响较小，这表明针对适当区域的CCR 5抑制可能使抑制高度HIV-1特异性，同时保留CC趋化因子-CCR 5相互作用。目前的数据描绘的残基与CCR 5抑制剂的CCR 5的残基相互作用，不仅有助于设计更有效的和更多的HIV-1特异性的CCR 5抑制剂，但也提供了新的见解CC-趋化因子-CCR 5的相互作用的动力学和CCR 5参与的HIV-1的细胞进入的过程中的机制。
We have characterized the structural and molecular interactions of CC-chemokine receptor 5 (CCR5) with three CCR5 inhibitors active against R5 human immunodeficiency virus type 1 (HIV-1) including the potent in vitro and in vivo CCR5 inhibitor aplaviroc (AVC). The data obtained with saturation binding assays and structural analyses delineated the key interactions responsible for the binding of CCR5 inhibitors with CCR5 and illustrated that their binding site is located in a predominantly lipophilic pocket in the interface of extracellular loops and within the upper transmembrane (TM) domain of CCR5. Mutations in the CCR5 binding sites of AVC decreased gp120 binding to CCR5 and the susceptibility to HIV-1 infection, although mutations in TM4 and TM5 that also decreased gp120 binding and HIV-1 infectivity had less effects on the binding of CC-chemokines, suggesting that CCR5 inhibition targeting appropriate regions might render the inhibition highly HIV-1-specific while preserving the CC chemokine-CCR5 interactions. The present data delineating residue by residue interactions of CCR5 with CCR5 inhibitors should not only help design more potent and more HIV-1-specific CCR5 inhibitors, but also give new insights into the dynamics of CC-chemokine-CCR5 interactions and the mechanisms of CCR5 involvement in the process of cellular entry of HIV-1.