PDBsum entry 2bhg

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protein Protein-protein interface(s) links
Hydrolase PDB id
Protein chains
194 a.a. *
184 a.a. *
Waters ×98
* Residue conservation analysis
PDB id:
Name: Hydrolase
Title: 3c protease from type a10(61) foot-and-mouth disease virus
Structure: Foot-and-mouth disease virus 3c protease. Chain: a, b. Engineered: yes. Mutation: yes
Source: Foot-and-mouth disease virus. Fmdv. Organism_taxid: 12110. Strain: a10(61). Expressed in: escherichia coli. Expression_system_taxid: 562.
1.9Å     R-factor:   0.218     R-free:   0.245
Authors: J.R.Birtley,P.Brick,S.Curry
Key ref:
J.R.Birtley et al. (2005). Crystal structure of foot-and-mouth disease virus 3C protease. New insights into catalytic mechanism and cleavage specificity. J Biol Chem, 280, 11520-11527. PubMed id: 15654079 DOI: 10.1074/jbc.M413254200
10-Jan-05     Release date:   04-Feb-05    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P03306  (POLG_FMDV1) -  Genome polyprotein
2332 a.a.
194 a.a.*
Protein chain
Pfam   ArchSchema ?
P03306  (POLG_FMDV1) -  Genome polyprotein
2332 a.a.
184 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 6 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class 1: Chains A, B: E.C.  - RNA-directed Rna polymerase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Nucleoside triphosphate + RNA(n) = diphosphate + RNA(n+1)
Nucleoside triphosphate
+ RNA(n)
= diphosphate
+ RNA(n+1)
   Enzyme class 2: Chains A, B: E.C.  - Picornain 3C.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Selective cleavage of Gln-|-Gly bond in the poliovirus polyprotein. In other picornavirus reactions Glu may be substituted for Gln, and Ser or Thr for Gly.
   Enzyme class 3: Chains A, B: E.C.  - L-peptidase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Autocatalytically cleaves itself from the polyprotein of the foot-and-mouth disease virus by hydrolysis of a Lys-|-Gly bond, but then cleaves host cell initiation factor eIF-4G at bonds -Gly-|-Arg- and -Lys-|-Arg-.
   Enzyme class 4: Chains A, B: E.C.  - Nucleoside-triphosphate phosphatase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: NTP + H2O = NDP + phosphate
+ H(2)O
+ phosphate
Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     proteolysis   1 term 
  Biochemical function     catalytic activity     2 terms  


DOI no: 10.1074/jbc.M413254200 J Biol Chem 280:11520-11527 (2005)
PubMed id: 15654079  
Crystal structure of foot-and-mouth disease virus 3C protease. New insights into catalytic mechanism and cleavage specificity.
J.R.Birtley, S.R.Knox, A.M.Jaulent, P.Brick, R.J.Leatherbarrow, S.Curry.
Foot-and-mouth disease virus (FMDV) causes a widespread and economically devastating disease of domestic livestock. Although FMDV vaccines are available, political and technical problems associated with their use are driving a renewed search for alternative methods of disease control. The viral RNA genome is translated as a single polypeptide precursor that must be cleaved into functional proteins by virally encoded proteases. 10 of the 13 cleavages are performed by the highly conserved 3C protease (3C(pro)), making the enzyme an attractive target for antiviral drugs. We have developed a soluble, recombinant form of FMDV 3C(pro), determined the crystal structure to 1.9-angstroms resolution, and analyzed the cleavage specificity of the enzyme. The structure indicates that FMDV 3C(pro) adopts a chymotrypsin-like fold and possesses a Cys-His-Asp catalytic triad in a similar conformation to the Ser-His-Asp triad conserved in almost all serine proteases. This observation suggests that the dyad-based mechanisms proposed for this class of cysteine proteases need to be reassessed. Peptide cleavage assays revealed that the recognition sequence spans at least four residues either side of the scissile bond (P4-P4') and that FMDV 3C(pro) discriminates only weakly in favor of P1-Gln over P1-Glu, in contrast to other 3C(pro) enzymes that strongly favor P1-Gln. The relaxed specificity may be due to the unexpected absence in FMDV 3C(pro) of an extended beta-ribbon that folds over the substrate binding cleft in other picornavirus 3C(pro) structures. Collectively, these results establish a valuable framework for the development of FMDV 3C(pro) inhibitors.
  Selected figure(s)  
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 reprinted by permission from the ASBMB: J Biol Chem (2005, 280, 11520-11527) copyright 2005.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21396941 S.Cui, J.Wang, T.Fan, B.Qin, L.Guo, X.Lei, J.Wang, M.Wang, and Q.Jin (2011).
Crystal structure of human enterovirus 71 3C protease.
  J Mol Biol, 408, 449-461.
PDB code: 3osy
20333533 C.Klopfleisch, L.Q.Minh, K.Giesow, S.Curry, and G.M.Keil (2010).
Effect of foot-and-mouth disease virus capsid precursor protein and 3C protease expression on bovine herpesvirus 1 replication.
  Arch Virol, 155, 723-731.  
19144641 C.C.Lee, C.J.Kuo, T.P.Ko, M.F.Hsu, Y.C.Tsui, S.C.Chang, S.Yang, S.J.Chen, H.C.Chen, M.C.Hsu, S.R.Shih, P.H.Liang, and A.H.Wang (2009).
Structural basis of inhibition specificities of 3C and 3C-like proteases by zinc-coordinating and peptidomimetic compounds.
  J Biol Chem, 284, 7646-7655.
PDB codes: 2ztx 2zty 2ztz 2zu1 2zu2 2zu3 2zu4 2zu5
19264613 C.H.Williams, M.Panayiotou, G.D.Girling, C.I.Peard, S.Oikarinen, H.Hyöty, and G.Stanway (2009).
Evolution and conservation in human parechovirus genomes.
  J Gen Virol, 90, 1702-1712.  
18633492 G.K.Busch, E.W.Tate, P.R.Gaffney, E.Rosivatz, R.Woscholski, and R.J.Leatherbarrow (2008).
Specific N-terminal protein labelling: use of FMDV 3C pro protease and native chemical ligation.
  Chem Commun (Camb), (), 3369-3371.  
16979372 S.Curry, N.Roqué-Rosell, P.A.Zunszain, and R.J.Leatherbarrow (2007).
Foot-and-mouth disease virus 3C protease: recent structural and functional insights into an antiviral target.
  Int J Biochem Cell Biol, 39, 1-6.  
17065215 T.R.Sweeney, N.Roqué-Rosell, J.R.Birtley, R.J.Leatherbarrow, and S.Curry (2007).
Structural and mutagenic analysis of foot-and-mouth disease virus 3C protease reveals the role of the beta-ribbon in proteolysis.
  J Virol, 81, 115-124.
PDB code: 2j92
  17671377 X.Tian, Y.Feng, T.Zhao, H.Peng, J.Yan, J.Qi, F.Jiang, K.Tian, and F.Gao (2007).
Molecular cloning, expression, purification and crystallographic analysis of PRRSV 3CL protease.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 63, 720-722.  
16973591 A.Nayak, I.G.Goodfellow, K.E.Woolaway, J.Birtley, S.Curry, and G.J.Belsham (2006).
Role of RNA structure and RNA binding activity of foot-and-mouth disease virus 3C protein in VPg uridylylation and virus replication.
  J Virol, 80, 9865-9875.  
16641296 C.E.Zeitler, M.K.Estes, and B.V.Venkataram Prasad (2006).
X-ray crystallographic structure of the Norwalk virus protease at 1.5-A resolution.
  J Virol, 80, 5050-5058.
PDB codes: 2fyq 2fyr
17085042 J.R.Mesters, J.Tan, and R.Hilgenfeld (2006).
Viral enzymes.
  Curr Opin Struct Biol, 16, 776-786.  
16895471 M.N.James (2006).
The peptidases from fungi and viruses.
  Biol Chem, 387, 1023-1029.  
15858279 J.R.Birtley, and S.Curry (2005).
Crystallization of foot-and-mouth disease virus 3C protease: surface mutagenesis and a novel crystal-optimization strategy.
  Acta Crystallogr D Biol Crystallogr, 61, 646-650.  
16227288 K.Nakamura, Y.Someya, T.Kumasaka, G.Ueno, M.Yamamoto, T.Sato, N.Takeda, T.Miyamura, and N.Tanaka (2005).
A norovirus protease structure provides insights into active and substrate binding site integrity.
  J Virol, 79, 13685-13693.
PDB code: 1wqs
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.