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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Protein conformational dynamics in the mechanism of HIV-1 protease catalysis
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Protein conformational dynamics in the mechanism of HIV-1 protease catalysis

机译:HIV-1蛋白酶催化机制中的蛋白质构象动力学

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摘要

We have used chemical protein synthesis and advanced physical methods to probe dynamics-function correlations for the HIV-1 protease, an enzyme that has received considerable attention as a target for the treatment of AIDS. Chemical synthesis was used to prepare a series of unique analogues of the HIV-1 protease in which the flexibility of the "flap" structures (residues 37-61 in each monomer of the homodimeric protein molecule) was systematically varied. These analogue enzymes were further studied by X-ray crystallography, NMR relaxation, and pulse-EPR methods, in conjunction with molecular dynamics simulations. We show that conformational isomerization in the flaps is correlated with structural reorganization of residues in the active site, and that it is preorganization of the active site that is a rate-limiting factor in catalysis.
机译:我们已经使用化学蛋白质合成和先进的物理方法来探测HIV-1蛋白酶的动力学-功能相关性,该酶已作为治疗AIDS的目标受到了广泛关注。化学合成被用来制备一系列HIV-1蛋白酶的独特类似物,其中“翼”结构(同二聚体蛋白分子的每个单体中的残基37-61)的柔韧性被系统地改变。通过X射线晶体学,NMR弛豫和脉冲EPR方法,结合分子动力学模拟,进一步研究了这些类似酶。我们表明,襟翼中的构象异构化与活性位点中残基的结构重组相关,并且活性位点的预组织是催化中的限速因子。

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