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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 (3CL pro) 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 3CL pro from PEDV. Analysis of the PEDV 3CL pro structure and comparison to other coronaviral 3CL pro's from the same alpha-coronavirus phylogeny shows that the overall structures and active site architectures across 3CL pro'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) 3CL pro, (R)-16, to have inhibitor activity against PEDV 3CL pro, despite that SARS-3CL pro and PEDV 3CL pro share only 45.4% sequence identity. Structural comparison reveals that the majority of residues involved in (R)-16 binding to SARS-3CL pro are conserved in PEDV-3CL pro; however, the sequence variation and positional difference in the loop forming the S-2 pocket may account for large observed difference in IC 50 values. In conclusion, this work advances our understanding of the subtle, but important, differencesmore » in coronaviral 3CL pro architecture and contributes to the broader structural knowledge of coronaviral 3CL pro's.« less
Authors:
 [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:
1283059
Grant/Contract Number:
AC02-06CH11357
Type:
Accepted Manuscript
Journal Name:
Scientific Reports
Additional Journal Information:
Journal Volume: 6; Journal ID: ISSN 2045-2322
Publisher:
Nature Publishing Group
Research Org:
Purdue Univ., West Lafayette, IN (United States)
Sponsoring Org:
USDOE Office of Science (SC)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; coronavirus main proteinase; cov 3cl protease; 3clpro; design; drug discovery; x-ray crystallography