Cis/trans isomerization in HIV-1 capsid protein catalyzed by cyclophilin A: Insights from computational and theoretical studies
Cis/trans isomerization in HIV-1 capsid protein catalyzed by cyclophilin A: Insights from computational and theoretical studies
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DOI：
10.1002/prot.20135
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发表时间：
2004-08-15
影响因子：
2.9
通讯作者：
Agarwal, PK
中科院分区：
文献类型：
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作者：
Agarwal, PK
最近在酶亲环蛋白A （CypA）中发现了一个蛋白质振动网络，它与小肽底物的肽基脯氨酸顺/反异构化活性有关。这一网络可能对异构化反应的催化步骤有促进作用。这项工作介绍了人类免疫缺陷病毒1型（HIV-1）衣壳蛋白（CA(N)） N端结构域Gly89-Pro90肽键异构化过程中该网络的表征结果，这是一种天然存在的、与CypA生物学相关的蛋白底物。各种计算和理论研究被用来研究CypA-CA(N)复合物在异构化过程中的蛋白质动力学，在多个时间尺度上。这些结果为异构化的详细机制提供了见解，并证实了先前报道的与反应耦合的蛋白质振动网络的存在。在络合界面和界面远端的位置上保守的CypA残基构成了该网络的一部分。CypA有HIV-1相关的医学意义；将CypA与衣壳蛋白结合到病毒粒子中是HIV-1感染活性所必需的。相互作用能和动态相互关联计算用于CypA-CA(N)复合物中蛋白质-蛋白质相互作用的详细研究。结果表明，CA(N)残基His87-Ala-Gly-Pro-Ile-Ala92形成了与CypA残基的大部分相互作用。还发现了活性位点远端的新蛋白相互作用(CypA Arg148-CA（N) Gln95和CypA Arg148-CA(N) Asn121）。(C) 2004 Wiley-Liss, Inc。
A network of protein vibrations has recently been identified in the enzyme cyclophilin A (CypA) that is associated with its peptidylprolyl cis/trans isomerization activity of small peptide substrates. It has been suggested that this network may have a role in promoting the catalytic step during the isomerization reaction. This work presents the results from the characterization of this network during the isomerization of the Gly89-Pro90 peptide bond in the N-terminal domain of the capsid protein (CA(N)) from human immunodeficiency virus type 1 (HIV-1), which is a naturally occurring, biologically relevant protein substrate for CypA. A variety of computational and theoretical studies are utilized to investigate the protein dynamics of the CypA-CA(N) complex, at multiple time scales, during the isomerization step. The results provide insights into the detailed mechanism of isomerization and confirm the presence of previously reported network of protein vibrations coupled to the reaction. Conserved CypA residues at the complex interface and at positions distal to the interface form parts of this network. There is HIV-1 related medical interest in CypA; incorporation of CypA, complexed with the capsid protein, into the virion is required for the infectious activity of HIV-1. Interaction energy and dynamical cross-correlation calculations are used for a detailed investigation of the protein-protein interactions in the CypA-CA(N) complex. The results show that CA(N) residues His87-Ala-Gly-Pro-Ile-Ala92 form the majority of the interactions with CypA residues. New protein-protein interactions distal to the active site (CypA Arg148-CA(N) Gln95 and CypA Arg148-CA(N) Asn121) are also identified. (C) 2004 Wiley-Liss, Inc.