Three-dimensional model of a substrate-bound SARS chymotrypsin-like cysteine proteinase predicted by multiple molecular dynamics simulations: Catalytic efficiency regulated by substrate binding
Three-dimensional model of a substrate-bound SARS chymotrypsin-like cysteine proteinase predicted by multiple molecular dynamics simulations: Catalytic efficiency regulated by substrate binding
复制标题
DOI：
10.1002/prot.20249
复制
发表时间：
2004-12-01
影响因子：
2.9
通讯作者：
Pang, YP
中科院分区：
文献类型：
--
作者：
Pang, YP
严重急性呼吸综合征（SARS）是一种由新型冠状病毒引起的传染性和致命性疾病。负责SARS病毒复制的胰凝乳蛋白酶样半胱氨酸蛋白酶（CCP）的蛋白质序列已被确定为开发抗SARS药物的靶点。在这里，我报告了ATVRLQ（p1）A（p1 '）结合CCP 3D模型预测420个不同的分子动力学模拟（2.0 ns的每个模拟与1.0 fs的时间步长）。该理论模型在CCP的第一个X射线结构（PDB代码：1 Q2 W）发布之前在蛋白质数据库（PDB;代码：1 P76）发布。与在CCP和其他冠状病毒半胱氨酸蛋白酶的X射线结构中观察到的催化二联体相反，在底物结合CCP的理论模型中发现了包括Asp 187、His 41和Cys 145的催化三联体。CCP复合物的模拟表明，底物结合导致Asp 187和His 41截留的水分子的位移，从而将二分体转化为更有效的催化三联体。CCP复合物结构具有扩展的活性位点口袋，这对于抗SARS药物设计是有用的。此外，这项工作表明，多个分子动力学模拟是有效的，纠正错误，导致低序列同一性同源性建模。(C)2004 Wiley-Liss，Inc.
Severe acute respiratory syndrome (SARS) is a contagious and deadly disease caused by a new coronavirus. The protein sequence of the chymotrypsin-like cysteine proteinase (CCP) responsible for SARS viral replication has been identified as a target for developing anti-SARS drugs. Here, I report the ATVRLQ(p1)A(p1')-bound CCP 3D model predicted by 420 different molecular dynamics simulations (2.0 ns for each simulation with a 1.0-fs time step). This theoretical model was released at the Protein Data Bank (PDB; code: 1P76) before the release of the first X-ray structure of CCP (PDB code: 1Q2W). In contrast to the catalytic dyad observed in X-ray structures of CCP and other coronavirus cysteine proteinases, a catalytic triad comprising Asp187, His41, and Cys145 is found in the theoretical model of the substrate-bound CCP. The simulations of the CCP complex suggest that substrate binding leads to the displacement of a water molecule entrapped by Asp187 and His41, thus converting the dyad to a more efficient catalytic triad. The CCP complex structure has an expanded active-site pocket that is useful for anti-SARS drug design. In addition, this work demonstrates that multiple molecular dynamics simulations are effective in correcting errors that result from low-sequence-identity homology modeling. (C) 2004 Wiley-Liss, Inc.