PDBsum entry 2j92

Hydrolase

PDB id: 2j92

Contents

Protein chains

201 a.a.

185 a.a.

Waters ×109

References listed in PDB file

Key reference

Title

Structural and mutagenic analysis of foot-And-Mouth disease virus 3c protease reveals the role of the beta-Ribbon in proteolysis.

Authors

T.R.Sweeney, N.Roqué-Rosell, J.R.Birtley, R.J.Leatherbarrow, S.Curry.

Ref.

J Virol, 2007, 81, 115-124.

PubMed id

17065215

Abstract

The 3C protease (3C(pro)) 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 3C(pro), 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 beta-ribbon structure that is conformationally similar to equivalent regions on other picornaviral 3C proteases and some serine proteases. This beta-ribbon folds over the peptide binding cleft and clearly contributes to substrate recognition. Replacement of Cys142 at the tip of the beta-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 3C(pro) 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 beta-ribbon in catalytic activity and provide valuable insights for the design of FMDV 3C(pro) inhibitors.

Secondary reference #1

Title

Crystal structure of foot-And-Mouth disease virus 3c protease. New insights into catalytic mechanism and cleavage specificity.

Authors

J.R.Birtley, S.R.Knox, A.M.Jaulent, P.Brick, R.J.Leatherbarrow, S.Curry.

Ref.

J Biol Chem, 2005, 280, 11520-11527. [DOI no: 10.1074/jbc.M413254200]

PubMed id

15654079

Figure 2.
FIG. 2. Comparison of the active sites of 3C proteases shows that the catalytic triad found in FMDV 3C^pro most closely resembles that found in the serine protease chymotrypsin. To aid the comparison, the Cys163 side chain has been restored in the FMDV 3C^pro structure by modeling (since this is Ala in the crystal structure). Although the hydrogen-bonding geometry between Cys163 and His46 is nonideal, this may be due to small perturbations in the triad configuration resulting from the mutation to the smaller Ala side chain in the FMDV 3C^pro structure. The other crystal structures shown are chymotrypsin (Protein Data Bank code 4cha [PDB] (55)), HAV 3C^pro (Protein Data Bank code 1hav [PDB] (12)), and HRV 14 3C^pro (coordinates provided by D. Matthews).

Figure 6.
FIG. 6. Mapping of sequence conservation within 3C^pro among all seven serotypes of FMDV. A surface representation of the protein is shown with regions colored orange to represent sites of amino acid variation among 41 strains of FMDV 3C^pro spanning all seven serotypes; darker orange shading indicates higher degrees of variation. Model substrate is included to indicate P1-P4 positions.

The above figures are reproduced from the cited reference with permission from the ASBMB