HIV-1 Protease and Substrate Coevolution Validates the Substrate Envelope As the Substrate Recognition Pattern.
HIV-1 Protease and Substrate Coevolution Validates the Substrate Envelope As the Substrate Recognition Pattern.
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DOI：
10.1021/ct200668a
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发表时间：
2012-02-14
影响因子：
5.5
通讯作者：
Schiffer, Celia A.
中科院分区：
文献类型：
--
作者：
Oezen, Ayseguel;Haliloglu, Turkan;Schiffer, Celia A.
HIV-1蛋白酶的耐药性改变了分子识别事件的平衡，有利于底物加工与抑制剂结合。为了开发针对耐药变异体的强大抑制剂，需要破解这种平衡的密码。为此，需要揭示基质识别的原理。先前对WT蛋白酶-底物复合物的晶体学研究表明，尽管它们的序列同源性低，但底物在蛋白酶活性位点具有保守的共有体积。该共有体积被称为底物包封。最近通过考虑底物动力学对底物包膜进行了重新评估，据报道动态底物包膜可以更好地定义HIV-1蛋白酶的底物特异性。耐药性主要通过蛋白酶突变发生，偶尔伴有切割位点突变。本研究采用分子模拟和动力学模拟的方法，对3种共进化的蛋白酶-底物复合物（AP 2 VNC-p1 V82 A，LP 1 ′ Fp 1-p6 D30 N/N88 D和SP3′ Np 1-p6 D30 N/N88 D）的结构和动力学性质进行了研究。结果表明，如果没有增强，则在蛋白酶中存在耐药性突变的情况下，这些切割位点突变保留了底物包膜。蛋白酶-底物复合物的构象和突变集合的研究验证了底物包膜作为HIV-1蛋白酶的底物识别基序。底物包膜假说允许阐明多蛋白切割位点中可能的耐药突变模式。
Drug resistance of HIV-1 protease alters the balance in the molecular recognition events in favor of substrate processing versus inhibitor binding. To develop robust inhibitors targeting ensembles of drug-resistant variants, the code of this balance needs to be cracked. For this purpose, the principles governing the substrate recognition are required to be revealed. Previous crystallographic studies on the WT protease–substrate complexes showed that the substrates have a conserved consensus volume in the protease active site despite their low sequence homology. This consensus volume is termed as the substrate envelope. The substrate envelope was recently reevaluated by taking the substrate dynamics into account, and the dynamic substrate envelope was reported to better define the substrate specificity for HIV-1 protease. Drug resistance occurs mostly through mutations in the protease, occasionally accompanied by cleavage site mutations. In this study, three coevolved protease–substrate complexes (AP2VNC-p1V82A, LP1′Fp1-p6D30N/N88D, and SP3′Np1-p6D30N/N88D) were investigated for structural and dynamic properties by molecular modeling and dynamics simulations. The results show the substrate envelope is preserved by these cleavage site mutations in the presence of drug-resistance mutations in the protease, if not enhanced. This study on the conformational and mutational ensembles of protease–substrate complexes validates the substrate envelope as the substrate recognition motif for HIV-1 protease. The substrate envelope hypothesis allows for the elucidation of possible drug resistance mutation patterns in the polyprotein cleavage sites.
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