Model of human butyrylcholinesterase tetramer by homology modeling and dynamics simulation.
Model of human butyrylcholinesterase tetramer by homology modeling and dynamics simulation.
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DOI：
10.1021/jp8114995
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发表时间：
2009-05-07
期刊：
影响因子：
--
通讯作者：
Zhan CG
中科院分区：
文献类型：
--
作者：
Pan Y;Muzyka JL;Zhan CG
人丁酰胆碱酯酶（BChE）突变体对可卡因具有高活性，将非常有希望作为治疗可卡因滥用和过量的药物。希望设计在人体循环中具有长半衰期的重组BChE突变体。研究表明，BChE亚基可以通过含有富含脯氨酸的连接结构域（PRAD）的肽组装成稳定的四聚体。在本研究中，基于显式水溶剂化体系的同源建模和分子动力学（MD）模拟，构建了BChE四聚体与具有不同序列的PRAD复合的模型。三维模型使我们能够了解BChE亚基如何排列在四聚体中，以及BChE的四聚化结构域如何与PRAD结合形成稳定的人BChE四聚体。已经表明，位于BChE的C-末端的六个保守的疏水残基负责BChE的四聚化结构域和PRAD之间的关键静电和疏水相互作用。模拟的四聚体结构表明，三个残基，即Phe 547，Met 554和Phe 561，突变为其他疏水残基可能有利于增加BChE的四聚体结构域和PRAD之间的结合。因此，从这项研究中获得的详细结构的见解可能是有价值的合理设计的重组BChE四聚体在循环中具有较长的停留时间。
A mutant of human butyrylcholinesterase (BChE) with high activity against cocaine would be highly promising as a drug for therapeutic treatment of cocaine abuse and overdose. It is desirable to design a recombinant BChE mutant with a long half-life in human circulation. Studies showed that BChE subunits can be assembled by a peptide containing the proline-rich attachment domain (PRAD) to form a stable tetramer. The models of BChE tetramer complexed with PRAD with various sequences have been constructed, in the present study, based on homology modeling and molecular dynamics (MD) simulation of explicit water-solvated systems. The 3D models enable us to understand how the BChE subunits are arranged in the tetramer and how the tetramerization domain of BChE is associated with PRAD to form stable tetramer of human BChE. It has been shown that the six conserved hydrophobic residues located on the C-terminal of BChE are responsible for the key electrostatic and hydrophobic interactions between the tetramerization domain of BChE and PRAD. The simulated tetramer structures suggest that mutation of three residues, i.e. Phe547, Met554, and Phe561, to other hydrophobic residues may be beneficial for increasing the binding between the tetramerization domain of BChE and PRAD. Thus, the detailed structural insights obtained from this study may be valuable for rational design of a recombinant BChE tetramer with a longer residence time in circulation.
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影响因子：
3.3
作者：
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通讯作者：
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