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Homology modeling and molecular dynamics study of GSK3/SHAGGY-like kinase

机译:GSK3 / SHAGGY样激酶的同源性建模和分子动力学研究

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Although the GSK3/SHAGGY-Kke kinase is a highly conserved serine/threonine kinase implicated in many signaling pathways in eukary-otes, the lack of knowledge of its three-dimensional (3D) structure has hindered efforts to understand the binding specificities of substrate and catalytic mechanism. To understand the structure-activity relationships, the protein 3D structure was built by using homology modeling based on the known X-ray diffraction structure of Glycogen synthase kinase-3β (Gsk3β) and the model structure was further refined using unrestrained molecular dynamics simulations. The research indicates that the general 3D organization of the GSK3/SHAGGY-like kinase is a typical kinase family and comprises an N-terminal domain of β-sheet and a larger C-terminal domain mainly constituted by α-helix. In order to understand the molecular interactions between the natural substrate-ATP and GSK3/SHAGGY-like kinase, a 3D model of the complex ATP-GSK3/SHAGGY-like kinase is developed by molecular docking program, which is helpful to guide the experimental realization and the new mutant designs as well. One important finding is that the identification of the key binding-site residue of Lys69 which plays an important role in the catalysis of GSK3/SHAGGY-like kinase and this is in consistent with experimental observation.
机译:尽管GSK3 / SHAGGY-Kke激酶是高度保守的丝氨酸/苏氨酸激酶,与真核生物的许多信号传导途径有关,但缺乏对其三维(3D)结构的了解却阻碍了人们对底物和多肽结合特异性的理解。催化机制。为了了解结构-活性之间的关系,基于已知的糖原合酶激酶-3β(Gsk3β)的X射线衍射结构,通过同源性建模,构建了蛋白质3D结构,并使用不受约束的分子动力学模拟进一步完善了模型结构。研究表明,GSK3 / SHAGGY样激酶的一般3D组织是一个典型的激酶家族,包含β-sheet的N端结构域和主要由α-螺旋组成的较大C端结构域。为了了解天然底物ATP与GSK3 / SHAGGY样激酶之间的分子相互作用,通过分子对接程序建立了复杂的ATP-GSK3 / SHAGGY样激酶的3D模型,有助于指导实验实现以及新的突变体设计。一个重要发现是鉴定Lys69的关键结合位点残基,该残基在催化GSK3 / SHAGGY样激酶中起重要作用,这与实验观察一致。

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