Crystal structure of human enterovirus 71 3C protease

  • Cui S
  • Wang J
  • Fan T
 et al. 
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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 approximately 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 (3C(pro)) 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 3C(pro) make it an appealing target for antiviral drug development. We determined the first crystal structure of EV71 3C(pro) and analyzed its enzymatic activity. The crystal structure shows that EV71 3C(pro) has a typical chymotrypsin-like fold that is common in picornaviral 3C(pro). Strikingly, we found an important surface loop, also denoted as beta-ribbon, which adopts a novel open conformation in EV71 3C(pro). We identified two important residues located at the base of the beta-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 3C(pro) proteolytic activities. In summary, our work provides the first structural insight into EV71 3C(pro), including a mobile beta-ribbon, which is relevant to the proteolytic mechanism. Our data also provides a framework for structure-guided inhibitor design against EV71 3C(pro).

Author-supplied keywords

  • Amino Acid Sequence
  • Crystallography, X-Ray
  • Cysteine Endopeptidases/ chemistry/ metabolism
  • Enterovirus A, Human/ enzymology
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Protein Structure, Tertiary
  • RNA, Viral/genetics
  • Sequence Analysis, DNA
  • Sequence Homology, Amino Acid
  • Viral Proteins/ chemistry/ metabolism

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Authors

  • S Cui

  • J Wang

  • T Fan

  • B Qin

  • L Guo

  • X Lei

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