Crystal structure of human enterovirus 71 3C protease |
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Authors: | Cui Sheng Wang Jing Fan Tingting Qin Bo Guo Li Lei Xiaobo Wang Jianwei Wang Meitian Jin Qi |
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Affiliation: | 1 State Key Laboratory for Molecular Virology and Genetic Engineering, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, People's Republic of China2 Swiss Light Source at Paul Scherrer Institute, CH-5232 Villigen, Switzerland |
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Abstract: | Human enterovirus 71 (EV71) is the major pathogen that causes hand, foot and mouth disease that particularly affects young children. Growing hand, foot and mouth disease outbreaks were observed worldwide in recent years and caused devastating losses both economically and politically. However, vaccines or effective drugs are unavailable to date. The genome of EV71 consists of a positive sense, single-stranded RNA of ∼ 7400 bp, encoding a large precursor polyprotein that requires proteolytic processing to generate mature viral proteins. The proteolytic processing mainly depends on EV71 3C protease (3Cpro) that possesses both proteolysis and RNA binding activities, which enable the protease to perform multiple tasks in viral replication and pathogen-host interactions. The central roles played by EV71 3Cpro make it an appealing target for antiviral drug development. We determined the first crystal structure of EV71 3Cpro and analyzed its enzymatic activity. The crystal structure shows that EV71 3Cpro has a typical chymotrypsin-like fold that is common in picornaviral 3Cpro. Strikingly, we found an important surface loop, also denoted as β-ribbon, which adopts a novel open conformation in EV71 3Cpro. We identified two important residues located at the base of the β-ribbon, Gly123 and His133, which form hinges that govern the intrinsic flexibility of the ribbon. Structure-guided mutagenesis studies revealed that the hinge residues are important to EV71 3Cpro proteolytic activities. In summary, our work provides the first structural insight into EV71 3Cpro, including a mobile β-ribbon, which is relevant to the proteolytic mechanism. Our data also provides a framework for structure-guided inhibitor design against EV71 3Cpro. |
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Keywords: | EV71, human enterovirus 71 HFMD, hand, foot and mouth disease 3Cpro, 3C protease FMDV, foot-and-mouth disease virus HAV, hepatitis A virus PV, poliovirus HRV, human rhinovirus CVB, coxsackievirus B ASU, asymmetric unit SARS-CoV, severe acute respiratory syndrome-coronavirus WT, wild-type PDB, Protein Data Bank SLS, Swiss Light Source |
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