Peptide Triazole Inactivators of HIV-1 Utilize a Conserved Two-Cavity Binding Site at the Junction of the Inner and Outer Domains of Env gp120.
Peptide Triazole Inactivators of HIV-1 Utilize a Conserved Two-Cavity Binding Site at the Junction of the Inner and Outer Domains of Env gp120.
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DOI：
10.1021/acs.jmedchem.5b00073
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发表时间：
2015-05-14
影响因子：
7.3
通讯作者：
Chaiken, Irwin
中科院分区：
文献类型：
--
作者：
Aneja, Rachna;Rashad, Adel A.;Li, Huiyuan;Sundaram, Ramalingam Venkat Kalyana;Duffy, Caitlin;Bailey, Lauren D.;Chaiken, Irwin
我们采用协同诱变、合成设计和柔性对接的方法研究了HIV-1的多肽三氮唑(PT)灭活剂遇到的env gp120的结构机制。先前的研究结果表明，PT类抑制物抑制了Env上CD4和辅助受体位点的结合，并触发gp120脱落，导致细胞非依赖性不可逆病毒灭活。尽管有这些诱人的抗HIV-1表型，但对PT-gp120结合机制的结构理解还不完整。在这里，我们发现PT在gp120蛋白的内域和外域的交界处结合了两个抑制环部分。结果表明，两个gp120空腔的结合如何协同抑制受体和辅受体的结合，并以构象方式捕获处于不稳定状态的蛋白质。双腔模型具有小分子gp120抑制剂结合位点的共同特征，为进一步设计基于PT药效团的模拟肽HIV-1灭活剂提供了指导。
We used coordinated mutagenesis, synthetic design, and flexible docking to investigate the structural mechanism of Env gp120 encounter by peptide triazole (PT) inactivators of HIV-1. Prior results demonstrated that the PT class of inhibitors suppresses binding at both CD4 and coreceptor sites on Env and triggers gp120 shedding, leading to cell-independent irreversible virus inactivation. Despite these enticing anti-HIV-1 phenotypes, structural understanding of the PT–gp120 binding mechanism has been incomplete. Here we found that PT engages two inhibitor ring moieties at the junction between the inner and outer domains of the gp120 protein. The results demonstrate how combined occupancy of two gp120 cavities can coordinately suppress both receptor and coreceptor binding and conformationally entrap the protein in a destabilized state. The two-cavity model has common features with small molecule gp120 inhibitor binding sites and provides a guide for further design of peptidomimetic HIV-1 inactivators based on the PT pharmacophore.
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影响因子：
3.3
作者：
Bastian AR;Contarino M;Bailey LD;Aneja R;Moreira DR;Freedman K;McFadden K;Duffy C;Emileh A;Leslie G;Jacobson JM;Hoxie JA;Chaiken I
通讯作者：
Chaiken I
影响因子：
5.4
作者：
Guo, Q;Ho, HT;Lin, PF
通讯作者：
Lin, PF
影响因子：
2.7
作者：
Gopi, Hosahudya;Cocklin, Simon;Pirrone, Vanessa;McFadden, Karyn;Tuzer, Ferit;Zentner, Isaac;Ajith, Sandya;Baxter, Sabine;Jawanda, Navneet;Krebs, Fred C.;Chaiken, Irwin M.
通讯作者：
Chaiken, Irwin M.
影响因子：
5.4
作者：
Dey, Barna;Pancera, Marie;Wyatt, Richard
通讯作者：
Wyatt, Richard
DOI：
10.1126/science.1175868
发表时间：
2009-11-20
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Chen L;Kwon YD;Zhou T;Wu X;O'Dell S;Cavacini L;Hessell AJ;Pancera M;Tang M;Xu L;Yang ZY;Zhang MY;Arthos J;Burton DR;Dimitrov DS;Nabel GJ;Posner MR;Sodroski J;Wyatt R;Mascola JR;Kwong PD
通讯作者：
Kwong PD