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Journal of Virology, January 2007, p. 115-124, Vol. 81, No. 1
0022-538X/07/$08.00+0     doi:10.1128/JVI.01587-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Structural and Mutagenic Analysis of Foot-and-Mouth Disease Virus 3C Protease Reveals the Role of the ß-Ribbon in Proteolysis{triangledown}

Trevor R. Sweeney,1 Núria Roqué-Rosell,2 James R. Birtley,1 Robin J. Leatherbarrow,2 and Stephen Curry1*

Biophysics Section, Division of Cell and Molecular Biology, Blackett Laboratory,1 Biological and Biophysical Chemistry Section, Department of Chemistry, Imperial College, Exhibition Road, London SW7 2AZ, United Kingdom2

Received 25 July 2006/ Accepted 11 October 2006

The 3C protease (3Cpro) from foot-and-mouth disease virus (FMDV), the causative agent of a widespread and economically devastating disease of domestic livestock, is a potential target for antiviral drug design. We have determined the structure of a new crystal form of FMDV 3Cpro, a chymotrypsin-like cysteine protease, which reveals features that are important for catalytic activity. In particular, we show that a surface loop which was disordered in previous structures adopts a ß-ribbon structure that is conformationally similar to equivalent regions on other picornaviral 3C proteases and some serine proteases. This ß-ribbon folds over the peptide binding cleft and clearly contributes to substrate recognition. Replacement of Cys142 at the tip of the ß-ribbon with different amino acids has a significant impact on enzyme activity and shows that higher activity is obtained with more hydrophobic side chains. Comparison of the structure of FMDV 3Cpro with homologous enzyme-peptide complexes suggests that this correlation arises because the side chain of Cys142 contacts the hydrophobic portions of the P2 and P4 residues in the peptide substrate. Collectively, these findings provide compelling evidence for the role of the ß-ribbon in catalytic activity and provide valuable insights for the design of FMDV 3Cpro inhibitors.

* Corresponding author. Mailing address: Biophysics Section, Blackett Laboratory, Imperial College, London SW7 2AZ, United Kingdom. Phone: 44-20-7954-7632. Fax: 44-20-7589-0191. E-mail: s.curry{at}imperial.ac.uk.

{triangledown} Published ahead of print on 25 October 2006.

Journal of Virology, January 2007, p. 115-124, Vol. 81, No. 1
0022-538X/07/$08.00+0     doi:10.1128/JVI.01587-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Someya, Y., Takeda, N. (2009). Insights into the Enzyme-Substrate Interaction in the Norovirus 3C-like Protease. J Biochem 146: 509-521 [Abstract] [Full Text]  
  • Tully, D. C., Fares, M. A. (2009). Shifts in the Selection-Drift Balance Drive the Evolution and Epidemiology of Foot-and-Mouth Disease Virus. J. Virol. 83: 781-790 [Abstract] [Full Text]  


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