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Title: X-ray structure and inhibition of 3C-like protease from porcine epidemic diarrhea virus

Porcine epidemic diarrhea virus (PEDV) is a coronavirus that infects pigs and can have mortality rates approaching 100% in piglets, causing serious economic impact. The 3C-like protease (3CLpro) is essential for the coronaviral life cycle and is an appealing target for the development of therapeutics. We report the expression, purification, crystallization and 2.10 angstrom X-ray structure of 3CLpro from PEDV. Analysis of the PEDV 3CLpro structure and comparison to other coronaviral 3CLpro's from the same alpha-coronavirus phylogeny shows that the overall structures and active site architectures across 3CLpro's are conserved, with the exception of a loop that comprises the protease S-2 pocket. We found a known inhibitor of severe acute respiratory syndrome coronavirus (SARS-CoV) 3CLpro, (R)-16, to have inhibitor activity against PEDV 3CLpro, despite that SARS-3CLpro and PEDV 3CLpro share only 45.4% sequence identity. Structural comparison reveals that the majority of residues involved in (R)-16 binding to SARS-3CLpro are conserved in PEDV-3CLpro; however, the sequence variation and positional difference in the loop forming the S-2 pocket may account for large observed difference in IC50 values. In conclusion, this work advances our understanding of the subtle, but important, differences in coronaviral 3CLpro architecture and contributes to the broader structural knowledge ofmore » coronaviral 3CLpro's.« less
 [1] ;  [2] ;  [1]
  1. Purdue Univ., West Lafayette, IN (United States). Dept. of Chemistry, Dept. of Biological Sciences, Centers for Cancer Research & Drug Discovery
  2. Purdue Univ., West Lafayette, IN (United States). Dept. of Biological Sciences
Publication Date:
OSTI Identifier:
Grant/Contract Number:
Accepted Manuscript
Journal Name:
Scientific Reports
Additional Journal Information:
Journal Volume: 6; Journal ID: ISSN 2045-2322
Nature Publishing Group
Research Org:
Purdue Univ., West Lafayette, IN (United States)
Sponsoring Org:
USDOE Office of Science (SC)
Country of Publication:
United States
59 BASIC BIOLOGICAL SCIENCES coronavirus main proteinase; cov 3cl protease; 3clpro; design; drug discovery; x-ray crystallography