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Virology:SARS蛋白水解酶研究

来源:中科院上海药物研究所 2009-05-26 08:35

近日,中科院上海药物所药理三室沈旭研究员课题组与药物发现与设计中心(DDDC)蒋华良研究员课题组合作,博士生胡天岑、张余等人研究发现,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,通过晶体结构分析,他们系统研究了“3CL水解酶酶活”与“聚集状态”的关系,相应成果发表在最新一期的《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。

此次的新发现,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。(生物谷Bioon.com)

生物谷推荐原始出处:

Virology Volume 388, Issue 2, 5 June 2009, Pages 324-334

Two adjacent mutations on the dimer interface of SARS coronavirus 3C-like protease cause different conformational changes in crystal structure

Tiancen Hua, 1, Yu Zhanga, 1, Lianwei Lia, Kuifeng Wanga, Shuai Chena, Jing Chena, Jianping Dingb, Hualiang Jianga, ,  and Xu Shena, ,

aDrug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai 201203, China
bState Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China

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.

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