Picornain 3C

 

Foot-and-Mouth Disease Virus (FMDV) causes an economically devastating disease of domestic livestock. The viral RNA is translated as a single polypeptide precursor and must be cleaved into functional proteins by virally encoded proteases. 10 of the 13 cleavages are performed by the highly conserved FMDV 3C Protease. Foot-and-Mouth Disease 3C Protease (this entry) catalyses 3 different reactions. It is an RNA polymerase, selectively cleaves Xaa-Gln and Xaa-Glu amide bonds and autocatalytically cleaves itself from the polyprotein of the foot-and-mouth disease virus by hydrolysis of a Lys-Gly amide bond. It can also cleave host cell initiation factor eIF-4G at amide bonds Gly-Arg and Lys-Arg.

 

Reference Protein and Structure

Sequence
P03306 UniProt (2.7.7.48, 3.4.22.28, 3.4.22.46, 3.6.1.15) IPR000199 (Sequence Homologues) (PDB Homologues)
Biological species
Foot-and-mouth disease virus (strain A10-61) (Virus) Uniprot
PDB
2bhg - 3C protease from type A10(61) foot-and-mouth disease virus (1.9 Å) PDBe PDBsum 2bhg
Catalytic CATH Domains
2.40.10.10 CATHdb (see all for 2bhg)
Click To Show Structure

Enzyme Reaction (EC:3.4.22.28)

Gln-Gly
CHEBI:73848ChEBI
+
water
CHEBI:15377ChEBI
→
L-glutamine
CHEBI:18050ChEBI
+
glycine
CHEBI:15428ChEBI
Alternative enzyme names: 3C protease, 3C proteinase, Coxsackievirus 3C proteinase, Cysteine proteinase 3C, Foot-and-mouth protease 3C, Foot-and-mouth-disease virus proteinase 3C, Hepatitis A virus 3C proteinase, Picornavirus endopeptidase 3C, Poliovirus protease 3C, Poliovirus proteinase 3C, Protease 3C, Rhinovirus protease 3C, Rhinovirus proteinase 3C, Tomato ringspot nepovirus 3C-related protease,

Enzyme Mechanism

Introduction

Foot-and-Mouth Disease Virus has a chymotrypsin-like fold and possesses a Cys-His-Asp catalytic triad, in a similar conformation to the Ser-His-Asp. His 46 acts as a general base, deprotonating Cys 163. Cys 163 performs nucleophilic attack on the carbonyl carbon of the amide bond. This results in a tetrahedral transition state. Protonated His 46 is stabilised by electrostatic interactions with Asp 84. Ser 182 stabilises the conformation of Asp 84 The tetrahedral transition state collapses, forming an acyl-enzyme and His 46 acts as a general acid, protonating the amide leaving group. His 46 acts as a general base, deprotonating a water molecule. The activated water molecule performs nucleophilic attack upon the acyl enzyme, forming a tetrahedral transition state. The tetrahedral transition state collapses, forming the acid component of the substrate and Cys 163. His 46 acts as a general acid, protonating the leaving group Cys 163.

Catalytic Residues Roles

UniProt PDB* (2bhg)
His1695 His46(47)A 1: His 64 acts as a general base, deprotonating Cys 163. 2: The tetrahedral transition state formed collapses and His 46 acts as a general acid, protonating the amide leaving group. 3: His 46 acts as a general base, deprotonating a water molecule. 4: The tetrahedral transition state formed collapses and His 46 acts as a general acid, protonating the leaving group Cys 163. proton shuttle (general acid/base)
Asp1733 Asp84(85)A Asp 84 stabilises protonated His 46 through electrostatic interactions. electrostatic stabiliser
Cys1812 Ala163(164)A Cys 163 performs nucleophilic attack on the carbonyl carbon of the amide bond. covalent catalysis
Ser1831 Ser182(183)A Ser 182 stabilises the conformation of Asp 84, allowing it to electrostatically interact with His 46. electrostatic stabiliser
*PDB label guide - RESx(y)B(C) - RES: Residue Name; x: Residue ID in PDB file; y: Residue ID in PDB sequence if different from PDB file; B: PDB Chain; C: Biological Assembly Chain if different from PDB. If label is "Not Found" it means this residue is not found in the reference PDB.

Chemical Components

References

  1. Birtley JR et al. (2005), J Biol Chem, 280, 11520-11527. Crystal Structure of Foot-and-Mouth Disease Virus 3C Protease: NEW INSIGHTS INTO CATALYTIC MECHANISM AND CLEAVAGE SPECIFICITY. DOI:10.1074/jbc.m413254200. PMID:15654079.

Step 1.

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Catalytic Residues Roles

Residue Roles
His46(47)A proton shuttle (general acid/base)
Ser182(183)A electrostatic stabiliser
Asp84(85)A electrostatic stabiliser
Ala163(164)A covalent catalysis

Chemical Components

Step 1.

Contributors

Fiona J. E. Morgan, Gemma L. Holliday