Evidence that a prominent cavity in the coiled coil of HIV type 1 gp41 is an attractive drug target
Evidence that a prominent cavity in the coiled coil of HIV type 1 gp41 is an attractive drug target
复制标题
DOI：
10.1073/pnas.95.26.15613
复制
发表时间：
1998-12-22
影响因子：
11.1
通讯作者：
Kim, PS
中科院分区：
文献类型：
--
作者：
Chan, DC;Chutkowski, CT;Kim, PS
合成 C 肽，对应于 HIV 1 型 (HIV-1) gp41 包膜蛋白的 C 螺旋，是 HIV-1 膜融合的有效抑制剂。一种这样的肽正在临床试验中。 gp41核心的晶体结构，在其提出的融合活性构象中，是螺旋发夹的三聚体，其中三个C螺旋紧靠中央卷曲线圈。每个 C 螺旋都显示出与卷曲线圈表面上三个对称相关的疏水空腔之一的特别显着的接触。我们表明，C 肽 C34 的抑制活性取决于其与卷曲线圈空腔结合的能力。此外，通过检查一系列具有修饰的空腔结合残基的 C34 肽变体，我们发现抑制效力的对数与相应螺旋发夹复合物的稳定性之间存在线性关系。我们的结果提供了强有力的证据，证明该卷曲螺旋腔是一个良好的药物靶点，并阐明了 C 肽抑制机制。他们还建议采用简单的定量分析方法来鉴定和评估类似的 HIV-1 进入抑制剂。
Synthetic C peptides, corresponding to the C helix of the HIV type 1 (HIV-1) gp41 envelope protein, are potent inhibitors of HIV-1 membrane fusion. One such peptide is in clinical trials. The crystal structure of the gp41 core, in its proposed fusion-active conformation, is a trimer of helical hairpins in which three C helices pack against a central coiled coil. Each C helix shows especially prominent contacts with one of three symmetry-related, hydrophobic cavities on the surface of the coiled coil. We show that the inhibitory activity of the C peptide C34 depends on its ability to bind to this coiled coil cavity. Moreover, examining a series of C34 peptide variants with modified cavity-binding residues, we find a linear relationship between the logarithm of the inhibitory potency and the stability of the corresponding helical-hairpin complexes. Our results provide strong evidence that this coiled-coil cavity is a good drug target and clarify the mechanism of C peptide inhibition. They also suggest simple, quantitative assays for the identification and evaluation of analogous inhibitors of HIV-1 entry.