HIV-1 protease-substrate coevolution in nelfinavir resistance.
HIV-1 protease-substrate coevolution in nelfinavir resistance.
复制标题
奈非那韦耐药中的 HIV-1 蛋白酶-底物协同进化。
DOI：
10.1128/jvi.00266-14
复制
发表时间：
2014
影响因子：
5.4
通讯作者：
Schiffer,CeliaA
中科院分区：
文献类型：
--
作者：
Kolli,Madhavi;Ozen,Ayşegül;Kurt-Yilmaz,Nese;Schiffer,CeliaA
对各种人类免疫缺陷病毒1型（HIV-1）蛋白酶抑制剂（PI）的耐药性挑战了治疗HIV-1感染个体和AIDS患者的疗法的有效性。病毒在蛋白酶（PR）内积累突变，使PI效力降低。偶尔，Gag序列也与PR切割位点的突变共同进化，导致耐药性。在这项研究中，我们研究了p1-p6切割位点与奈非那韦（NFV）耐药蛋白酶D30 N/N88 D突变的协同进化的结构基础，通过确定野生型和NFV耐药HIV-1蛋白酶与p1-p6底物肽变体L449 F和/或S451 N复合的晶体结构。残基30与底物相互作用的改变通过共同进化的L449 F和S451 N切割位点突变来补偿。这种在PR-P1-P6相互作用的相互依赖性增强了分子间的接触，并加强了整体适合的基板内的基板信封，可能使共同进化，以维持基板识别和切割的存在下PR耐药mutation.IMPORTANCEResistance人类免疫缺陷病毒1型（HIV-1）蛋白酶抑制剂的挑战治疗HIV-1感染的个人和艾滋病患者的有效性的治疗。在蛋白酶抑制剂的压力下选择的HIV-1蛋白酶突变使抑制剂效力降低。偶尔，Gag序列也会突变并与蛋白酶共同进化，有助于维持病毒适应性和耐药性。在这项研究中，我们研究了Gag p1-p6切割位点与耐奈非那韦（NFV）蛋白酶D30 N/N88 D突变的协同进化的结构基础。我们的结构分析揭示了蛋白酶-底物相互作用的相互依赖性，以及协同进化如何在蛋白酶耐药突变的存在下恢复底物识别和裂解。
Resistance to various human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs) challenges the effectiveness of therapies in treating HIV-1-infected individuals and AIDS patients. The virus accumulates mutations within the protease (PR) that render the PIs less potent. Occasionally, Gag sequences also coevolve with mutations at PR cleavage sites contributing to drug resistance. In this study, we investigated the structural basis of coevolution of the p1-p6 cleavage site with the nelfinavir (NFV) resistance D30N/N88D protease mutations by determining crystal structures of wild-type and NFV-resistant HIV-1 protease in complex with p1-p6 substrate peptide variants with L449F and/or S451N. Alterations of residue 30's interaction with the substrate are compensated by the coevolving L449F and S451N cleavage site mutations. This interdependency in the PR–p1-p6 interactions enhances intermolecular contacts and reinforces the overall fit of the substrate within the substrate envelope, likely enabling coevolution to sustain substrate recognition and cleavage in the presence of PR resistance mutations.IMPORTANCEResistance to human immunodeficiency virus type 1 (HIV-1) protease inhibitors challenges the effectiveness of therapies in treating HIV-1-infected individuals and AIDS patients. Mutations in HIV-1 protease selected under the pressure of protease inhibitors render the inhibitors less potent. Occasionally, Gag sequences also mutate and coevolve with protease, contributing to maintenance of viral fitness and to drug resistance. In this study, we investigated the structural basis of coevolution at the Gag p1-p6 cleavage site with the nelfinavir (NFV) resistance D30N/N88D protease mutations. Our structural analysis reveals the interdependency of protease-substrate interactions and how coevolution may restore substrate recognition and cleavage in the presence of protease drug resistance mutations.