Origins of resistance to the HIVgp41 viral entry inhibitor T20.
Origins of resistance to the HIVgp41 viral entry inhibitor T20.
复制标题
DOI：
10.1021/bi901915g
复制
发表时间：
2010-05-04
期刊：
影响因子：
2.9
通讯作者：
Rizzo, Robert C.
中科院分区：
文献类型：
--
作者：
McGillick, Brian E.;Balius, Trent E.;Mukherjee, Sudipto;Rizzo, Robert C.
靶向HIV蛋白gp 41的肽T20代表了被称为膜融合抑制剂的HIV药物类别中第一个被批准的成员。然而，通过临床使用T20导致耐药性的机制尚未得到很好的理解，因为结合复合物的结构仍不确定。在这份报告中，T20-gp 41复合物嵌入在一个明确的DOPC膜的原子级模型的构建和分子动力学模拟，结合能分析（MM-GBSA方法）进行描绘结构和能量的功能，有助于耐药性。T20与野生型gp 41的每残基结合足迹揭示了与临床观察到的抗性模式惊人一致的强分子间货车德瓦尔斯、库仑和H键相互作用。此外，模拟了7个有害的gp 41点突变（L33 Q、L33 S、G36 V、I37 K、V38 E、Q40 H和Q40 K），并且全部正确地显示结合降低，包括L33 Q和Q40 K是最有害的事实。七个模拟中的六个产生与可用的实验耐折性数据良好的定量一致性（r2 = 0.72，N=6）。能量分解、热图分析和差异（突变-野生型）足迹分析的结果表明：突变破坏了分子间氢键，并减少了与M19处gp 41的有利接触。带电突变（I37 K、Q40 K、V38 E）导致显著的库仑变化，从而降低有利的货车范德华相互作用。Q40 K比I37 K更有害，这是由于在初始（野生型）状态下与T20上的极性/带电补丁的相互作用差异。L33 S与L33 Q的耐药性可能涉及最终（突变）状态的侧链包装差异。这项工作的一个有价值的发现涉及鉴定T20的C-末端（WNWF基序）、gp 41上的残基（包括融合肽）和相邻膜中的头基之间的有利相互作用。结果表明，完整的T20结合位点将有助于形成稳定的复合物，这有助于解释为什么采用截短的gp 41构建体的先前研究报告C末端T20残基可能不与gp 41相互作用。从这项研究中得到的一个假设是，肽可以被设计成增加与膜和gp 41的有利接触，这将导致活性增强。
The peptide T20, which targets the HIV protein gp41, represents the first approved member in the HIV drug class known as membrane fusion inhibitors. However, mechanisms which lead to resistance through clinical use of T20 are not well-understood because the structure of the bound complex remains undetermined. In this report, an atomic-level model of a T20-gp41 complex embedded in an explicit DOPC membrane was constructed and molecular dynamics simulations, followed by binding energy analysis (MM-GBSA method) was performed to delineate structural and energetic features that contribute to drug resistance. Per-residue binding footprints for T20 with wildtype gp41 reveal strong intermolecular van der Waals, Coulombic, and H-bond interactions in striking agreement with clinically observed resistance patterns. In addition, seven deleterious gp41 point mutations (L33Q, L33S, G36V, I37K, V38E, Q40H, and Q40K) were simulated and all correctly showed decreases in binding, including the fact that L33Q and Q40K are most detrimental. Six out of the seven simulations yield good quantitative agreement (r2 = 0.72, N=6) with available experimental fold resistance data. Results from energy decomposition, heat-map analysis, and differential (mutant-wildtype) footprinting indicate: Mutations disrupt intermolecular H-bonding and reduce favorable contact with gp41 at M19. Charged mutations (I37K, Q40K, V38E) lead to significant Coulombic changes that reduce favorable van der Waals interactions. Q40K is more detrimental than I37K due to interaction differences with a polar/charged patch on T20 in the initial (wildtype) state. Resistance for L33S vs L33Q likely involves side-chain packing differences in the final (mutated) state. A valuable finding of the work involves identification of favorable interactions between the C-terminal end of T20 (WNWF motif), residues on gp41 (including the fusion peptide), and head groups in the adjacent membrane. The results suggests a complete T20 binding site would contribute to a stable complex, which could help to explain why prior studies, that employed truncated gp41 constructs, reported that C-terminal T20 residues may not interact with gp41. A hypothesis resulting from this study is that peptides could be designed to increase favorable contact with both the membrane and gp41 which would lead to enhanced activity.
登录
查看更多内容
影响因子：
7.3
作者：
Debnath, AK;Radigan, L;Jiang, SB
通讯作者：
Jiang, SB
影响因子：
64.5
作者：
Eckert, DM;Malashkevich, VN;Kim, PS
通讯作者：
Kim, PS
影响因子：
2.9
作者：
Carroll, Joan F.;Franks, Susan F.;Phelps, David R.
通讯作者：
Phelps, David R.
影响因子：
4.8
作者：
Champagne, Kelly;Shishido, Akira;Root, Michael J.
通讯作者：
Root, Michael J.
DOI：
10.1073/pnas.95.26.15613
发表时间：
1998-12-22
影响因子：
11.1
作者：
Chan, DC;Chutkowski, CT;Kim, PS
通讯作者：
Kim, PS