09候选院士最新封面文章 解密SARS蛋白水解酶

　　

生物通报道，近日，09候选院士，上海药物所药物发现与设计中心（DDDC）蒋华良研究员课题组与药理三室沈旭研究员课题组合作系统研究了“3CL水解酶酶活”与“聚集状态”的关系，相应成果Two adjacent mutations on the dimer interface of SARS coronavirus 3C-like protease cause different conformational changes in crystal structure发表在最新一期的《病毒学》（Virology, 2009, 388, 324-334）杂志上，并被列为封面文章予以介绍。

 

2003年全国爆发SARS期间，沈旭研究员和蒋华良研究员两个课题组通力合作，积极投入到“SARS病毒重要蛋白功能研究”中，迄今为止已取得一系列富有价值的成果，如发现并证实SARS病毒N蛋白与人CypA的作用是SARS病毒感染人体正常细胞的一个可能途径，为SARS病毒感染人体机理研究提供了新线索；发现SARS 3CLpro G11A突变体在晶体中以单体形式存在，并阐明了3CL蛋白酶二聚体的形成与稳定机制，发表在JBC上的相应结果被《自然中国》评为亮点论文（S. Chen, et al., JBC, 2008, 283, 554-564）。这一系列研究成果在国际上产生了一定的影响。

 

此次研究发现虽然Ser139和Phe140是SARS蛋白水解酶（SARS 3CLpro）二聚界面的相邻氨基酸，其突变可引起不同的酶的聚集状态和活性，即Ser139突变使酶以单聚形式存在，但却保持一定的酶学活性，而Phen140突变使酶以二聚形式存在，却丧失活性。这些新的发现，不仅为阐明SARS 3CLpro活性和催化机理提供了重要素材，而且为基于3CLpro为靶点的抗SARS及相关病毒的药物设计提供了新的研究策略。

生物通推荐原文检索：Two adjacent mutations on the dimer interface of SARS coronavirus 3C-like protease cause different conformational changes in crystal structure

【Abstract】

The 3C-like protease of SARS coronavirus (SARS-CoV 3CLpro) is vital for SARS-CoV replication and is a promising drug target. It has been extensively proved that only the dimeric enzyme is active. Here we discovered that two adjacent mutations (Ser139_Ala and Phe140_Ala) on the dimer interface resulted in completely different crystal structures of the enzyme, demonstrating the distinct roles of these two residues in maintaining the active conformation of SARS-CoV 3CLpro. S139A is a monomer that is structurally similar to the two reported monomers G11A and R298A. However, this mutant still retains a small fraction of dimer in solution, which might account for its remaining activity. F140A is a dimer with the most collapsed active pocket discovered so far, well-reflecting the stabilizing role of this residue. Moreover, a plausible dimerization mechanism was also deduced from structural analysis. Our work is expected to provide insight on the dimerization–function relationship of SARS-CoV 3CLpro.