Mechanism of action of cyclophilin a explored by metadynamics simulations.
Mechanism of action of cyclophilin a explored by metadynamics simulations.
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DOI：
10.1371/journal.pcbi.1000309
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发表时间：
2009-03
影响因子：
4.3
通讯作者：
Carloni, Paolo
中科院分区：
文献类型：
--
作者：
Leone, Vanessa;Lattanzi, Gianluca;Molteni, Carla;Carloni, Paolo
反式/顺式Pro异构化参与多种生物学过程，包括多种疾病的发生。在HIV-1衣壳蛋白(CA)中，这一过程发生在病毒粒子的脱壳和募集过程中，并由亲环素A(CypA)催化。在这里，我们使用元动力学模拟来研究CA的模型底物HAGPIA在水中及其目标蛋白CypA中的异构化。我们的结果允许我们提出一个新的机制假说，这与所有可用的分子生物学数据最终是一致的。肽基脯氨酰异构酶是一种普遍存在的酶，其作用在几个生物过程中是至关重要的，例如，在细胞信号传递和几种疾病的发病中，例如艾滋病毒感染。因此，这些异构酶是设计新药的有希望的靶点。为此，我们需要了解它们的分子作用机制。亲环素A是一种最具特征的肽基-脯氨酰异构酶。以往的研究表明，几个蛋白质区域在异构酶功能中的作用。然而，仍然有实验确定的蛋白质的重要部分，其在机制中的具体作用仍不清楚。在这里，我们通过对亲环素A和作为HIV-1衣壳蛋白一部分的底物多肽的广泛计算研究来解决这个问题。我们提出了一种新的整个酶过程的四步反应机制，这与所有现有的实验数据是一致的。此外，这些步骤可用作药物开发的目标，例如用于治疗艾滋病毒-1感染。
Trans/cis prolyl isomerisation is involved in several biological processes, including the development of numerous diseases. In the HIV-1 capsid protein (CA), such a process takes place in the uncoating and recruitment of the virion and is catalyzed by cyclophilin A (CypA). Here, we use metadynamics simulations to investigate the isomerization of CA's model substrate HAGPIA in water and in its target protein CypA. Our results allow us to propose a novel mechanistic hypothesis, which is finally consistent with all of the available molecular biology data. Peptidyl prolyl isomerases are ubiquitous enzymes whose actions are crucial in several biological processes, such as, for instance, in cellular signalling and in the onset of several diseases, e.g., HIV infection. Therefore, these isomerases are promising targets for the design of new drugs. For this purpose, we need to understand their molecular mechanism of action. One of the most characterized peptidyl prolyl isomerases is cyclophilin A. Previous studies characterized the roles of several protein regions in isomerase function. However, there are still experimentally identified important portions of the protein whose specific actions in the mechanism are still not known. Here, we address this problem by an extensive computational study of cyclophilin A and a substrate peptide that is part of the HIV-1 capside protein. We present a novel four-step mechanism of the whole enzymatic process, which is consistent with all of the available experimental data. Moreover, these steps can be used as targets for the development of drugs, e.g., for HIV-1 infection.
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影响因子：
2.9
作者：
BASHFORD, D;KARPLUS, M
通讯作者：
KARPLUS, M
影响因子：
2.9
作者：
Agarwal, PK
通讯作者：
Agarwal, PK
影响因子：
15
作者：
Hur, S;Bruice, TC
通讯作者：
Bruice, TC
DOI：
10.1038/nsb927
发表时间：
2003-06-01
期刊：
NATURE STRUCTURAL BIOLOGY
影响因子：
--
作者：
Howard, BR;Vajdos, FF;Hill, CP
通讯作者：
Hill, CP
影响因子：
4.4
作者：
BECKE, AD
通讯作者：
BECKE, AD