A binding pocket for a small molecule inhibitor of HIV-1 entry within the transmembrane helices of CCR5
A binding pocket for a small molecule inhibitor of HIV-1 entry within the transmembrane helices of CCR5
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DOI：
10.1073/pnas.090576697
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发表时间：
2000-05-09
影响因子：
11.1
通讯作者：
Moore, JP
中科院分区：
文献类型：
--
作者：
Dragic, T;Trkola, A;Moore, JP
HIV-1进入CD 4+细胞需要病毒包膜糖蛋白与CD 4和辅助受体如趋化因子受体CCR 5和CXCR 4的顺序相互作用。阻断这一过程的一种可行方法是使用辅助受体功能的小分子拮抗剂。已描述了一种针对CCR 5的此类抑制剂：TAK-779分子。为了促进进入抑制剂作为抗病毒药物的进一步开发，我们探索了TAK-779如何预防HIV-1感染。我们绘制了它与CCR 5相互作用的位点。我们发现TAK-779通过阻断病毒表面糖蛋白gp 120与CCR 5的相互作用，在膜融合阶段抑制HIV-1复制。我们在CCR 5的胞外结构域内未发现影响TAK-779抗病毒作用的氨基酸取代。然而，跨膜结构域的丙氨酸扫描诱变显示，CCR 5上TAK-779的结合位点位于受体的细胞外表面附近，在跨膜螺旋1、2、3和7之间形成的空腔内。
HIV-1 entry into CD4+ cells requires the sequential interactions of the viral envelope glycoproteins with CD4 and a coreceptor such as the chemokine receptors CCR5 and CXCR4. A plausible approach to blocking this process is to use small molecule antagonists of coreceptor function. One such inhibitor has been described for CCR5: the TAK-779 molecule. To facilitate the further development of entry inhibitors as antiviral drugs, we have explored how TAK-779 acts to prevent HIV-1 infection. and we have mapped its site of interaction with CCR5. We find that TAK-779 inhibits HIV-1 replication at the membrane fusion stage by blocking the interaction of the viral surface glycoprotein gp120 with CCR5. We could identify no amino acid substitutions within the extracellular domain of CCR5 that affected the antiviral action of TAK-779. However, alanine scanning mutagenesis of the transmembrane domains revealed that the binding site for TAK-779 on CCR5 is located near the extracellular surface of the receptor, within a cavity formed between transmembrane helices 1, 2, 3, and 7.