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威尔逊病蛋白核苷酸结合结构域的分子建模:ATP结合位点的定位、结构域动力学及主要疾病突变的潜在影响

Molecular modelling of the nucleotide-binding domain of Wilson's disease protein: location of the ATP-binding site, domain dynamics and potential effects of the major disease mutations.

作者信息

Efremov Roman G, Kosinsky Yuri A, Nolde Dmitry E, Tsivkovskii Ruslan, Arseniev Alexander S, Lutsenko Svetlana

机构信息

M. M. Shemyakin & Yu. A. Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Ul. Miklukho-Maklaya, 16/10, Moscow V-437, 117997 GSP, Russia.

出版信息

Biochem J. 2004 Aug 15;382(Pt 1):293-305. doi: 10.1042/BJ20040326.

Abstract

WNDP (Wilson's disease protein) is a copper-transporting ATPase that plays an essential role in human physiology. Mutations in WNDP result in copper accumulation in tissues and cause a severe hepato-neurological disorder known as Wilson's disease. Several mutations were surmised to affect the nucleotide binding and hydrolysis by WNDP; however, how the nucleotides bind to normal and mutated WNDP remains unknown. To aid such studies, we performed the molecular modelling of the spatial structure and dynamics of the ATP-binding domain of WNDP and its interactions with ATP. The three-dimensional models of this domain in two conformations were built using the X-ray structures of the Ca2+-ATPase in the E1 and E2 states. To study the functional aspects of the models, they were subjected to long-term molecular dynamics simulations in an explicit solvent; similar calculations were performed for the ATP-binding domain of Ca2+-ATPase. In both cases, we found large-scale motions that lead to significant changes of distances between several functionally important residues. The ATP docking revealed two possible modes of ATP binding: via adenosine buried in the cleft near residues H1069, R1151 and D1164, and via phosphate moiety 'anchored' by H-bonds with residues in the vicinity of catalytic D1027. Furthermore, interaction of ATP with both sites occurs if they are spatially close to each other. This may be achieved after relative domain motions of the 'closure' type observed in molecular dynamics simulations. The results provide a framework for analysis of disease mutations and for future mutagenesis studies.

摘要

WNDP(威尔逊病蛋白)是一种铜转运ATP酶,在人体生理过程中发挥着至关重要的作用。WNDP的突变会导致铜在组织中蓄积,并引发一种严重的肝神经疾病,即威尔逊病。据推测,有几种突变会影响WNDP的核苷酸结合和水解;然而,核苷酸如何与正常和突变的WNDP结合仍不清楚。为了辅助此类研究,我们对WNDP的ATP结合结构域的空间结构和动力学及其与ATP的相互作用进行了分子建模。利用Ca2 + -ATP酶在E1和E2状态下的X射线结构构建了该结构域两种构象的三维模型。为了研究模型的功能方面,在显式溶剂中对它们进行了长期分子动力学模拟;对Ca2 + -ATP酶的ATP结合结构域进行了类似的计算。在这两种情况下,我们都发现了大规模的运动,这些运动导致几个功能重要残基之间的距离发生显著变化。ATP对接揭示了两种可能的ATP结合模式:通过腺苷埋在靠近残基H1069、R1151和D1164的裂隙中,以及通过磷酸基团与催化性D1027附近的残基形成氢键“锚定”。此外,如果两个位点在空间上彼此靠近,ATP就会与它们两者发生相互作用。这可能在分子动力学模拟中观察到的“闭合”型相对结构域运动之后实现。这些结果为疾病突变分析和未来的诱变研究提供了一个框架。

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