Structural basis of HIV-1 maturation inhibitor binding and activity.
Structural basis of HIV-1 maturation inhibitor binding and activity.
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DOI：
10.1038/s41467-023-36569-y
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发表时间：
2023-03-04
影响因子：
16.6
通讯作者：
Polenova, Tatyana
中科院分区：
文献类型：
--
作者：
Sarkar, Sucharita;Zadrozny, Kaneil K.;Zadorozhnyi, Roman;Russell, Ryan W.;Quinn, Caitlin M.;Kleinpeter, Alex;Ablan, Sherimay;Meshkin, Hamed;Perilla, Juan R.;Freed, Eric O.;Ganser-Pornillos, Barbie K.;Pornillos, Owen;Gronenborn, Angela M.;Polenova, Tatyana
HIV-1成熟抑制剂（MI）、Bevirimat（BVM）及其类似物通过结合并稳定CACTD-SP1区域，干扰间隔肽1（SP1）从衣壳蛋白C末端结构域（CACTD）的催化裂解。正在开发MI作为替代药物，以加强目前的抗逆转录病毒疗法。虽然有希望，但其作用机制和相关的病毒抗性途径在分子，生物化学和结构水平上仍然知之甚少。我们报告了CACTD-SP1与BVM和/或组装辅因子肌醇六磷酸（IP 6）复合的微晶组装体的原子分辨率魔角旋转NMR结构。我们的研究结果揭示了一种机制，BVM破坏成熟，收紧6-螺旋束孔和淬火运动的SP1和同时绑定的IP 6。此外，BVM抗性SP1-A1 V和SP1-V7 A变体表现出不同的构象和结合特征。总之，我们的研究提供了一个结构的解释BVM电阻以及指导新的MI的设计。干扰Gag加工的HIV成熟抑制剂如贝韦瑞（BVM）正在成为替代抗逆转录病毒药物候选物。在这里，作者报告了跨越CA C-末端结构域和SP1区与BVM结合的HIV-1 Gag片段组装体的结构。
HIV-1 maturation inhibitors (MIs), Bevirimat (BVM) and its analogs interfere with the catalytic cleavage of spacer peptide 1 (SP1) from the capsid protein C-terminal domain (CACTD), by binding to and stabilizing the CACTD-SP1 region. MIs are under development as alternative drugs to augment current antiretroviral therapies. Although promising, their mechanism of action and associated virus resistance pathways remain poorly understood at the molecular, biochemical, and structural levels. We report atomic-resolution magic-angle-spinning NMR structures of microcrystalline assemblies of CACTD-SP1 complexed with BVM and/or the assembly cofactor inositol hexakisphosphate (IP6). Our results reveal a mechanism by which BVM disrupts maturation, tightening the 6-helix bundle pore and quenching the motions of SP1 and the simultaneously bound IP6. In addition, BVM-resistant SP1-A1V and SP1-V7A variants exhibit distinct conformational and binding characteristics. Taken together, our study provides a structural explanation for BVM resistance as well as guidance for the design of new MIs. HIV maturation inhibitors such as bevirimat (BVM) interfering with Gag processing are emerging as alternative anti-retroviral drug candidates. Here, the authors report structures of assemblies of HIV-1 Gag fragments spanning the CA C-terminal domain and SP1 region bound to BVM.
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影响因子：
2.2
作者：
Hou, Guangjin;Yan, Si;Trebosc, Julien;Amoureux, Jean-Paul;Polenova, Tatyana
通讯作者：
Polenova, Tatyana
影响因子：
5.4
作者：
Keller, Paul W.;Huang, Rick K.;Steven, Alasdair C.
通讯作者：
Steven, Alasdair C.
影响因子：
16.8
作者：
Lu, Manman;Russell, Ryan W.;Polenova, Tatyana
通讯作者：
Polenova, Tatyana
DOI：
10.1073/pnas.1917755117
发表时间：
2020-05-12
影响因子：
11.1
作者：
Gupta, Sebanti;Louis, John M.;Tycko, Robert
通讯作者：
Tycko, Robert
影响因子：
3
作者：
Mayne, Christopher G.;Saam, Jan;Schulten, Klaus;Tajkhorshid, Emad;Gumbart, James C.
通讯作者：
Gumbart, James C.