DB code: M00216

RLCP classification 1.13.30000.41 : Hydrolysis
CATH domain 3.90.70.- : Cathepsin B; Chain A
4.10.90.10 : Foot-And-Mouth Disease Virus, subunit 4
2.60.120.10 : Jelly Rolls
2.60.120.10 : Jelly Rolls
2.60.120.10 : Jelly Rolls
-.-.-.- :
-.-.-.- :
-.-.-.- :
-.-.-.- :
-.-.-.- :
-.-.-.- :
-.-.-.- :
2.40.10.10 : Thrombin, subunit H Catalytic domain
2.40.10.10 : Thrombin, subunit H Catalytic domain
3.90.-.- :
3.30.-.- :
1.20.-.- :
1.10.-.- :
E.C. 3.4.22.46 3.6.1.15 3.4.22.28 2.7.7.48
CSA 2bhg
M-CSA 2bhg
MACiE

CATH domain Related DB codes (homologues)
2.40.10.10 : Thrombin, subunit H M00139 D00214 M00167 D00426 M00133 D00428 D00429 D00430 D00431 D00432 D00433 D00434 D00435 M00227 M00209 D00194 D00197 D00211 D00212 D00216 M00212 D00224 D00497 M00217 D00528 D00848 D00850 D00851 D00852 D00855 M00152 M00155 M00157 M00181 M00315 M00316 M00317 M00348 M00349 T00074 T00410 T00411
2.60.120.10 : Jelly Rolls S00145 S00155 D00842 D00843 T00255 T00101

Uniprot Enzyme Name
UniprotKB Protein name Synonyms Contains MEROPS Pfam
P03306 Genome polyprotein
None Leader protease
(Lpro)
EC 3.4.22.46
Protein VP0 VP4-VP2
Protein VP4 P1A Virion protein 4
Protein VP2 P1B Virion protein 2
Protein VP3 P1C Virion protein 3
Protein VP1 P1D Virion protein 1
Protein 2A
(P2A)
P52
Protein 2B
(P2B)
Protein 2C
(P2C)
EC 3.6.1.15
Protein 3A
(P3A)
Protein 3B-1
(P3B-1)
Genome-linked protein VPg1
Protein 3B-2
(P3B-2)
Genome-linked protein VPg2
Protein 3B-3
(P3B-3)
Genome-linked protein VPg3
Picornain 3C
EC 3.4.22.28
Protease 3C
(P3C)
Protease P20B
RNA-directed RNA polymerase 3D-POL
(P3D-POL)
EC 2.7.7.48
P56A
C03.008 (Cysteine)
PF05408 (Peptidase_C28)
PF00548 (Peptidase_C3)
PF00680 (RdRP_1)
PF00073 (Rhv)
PF00910 (RNA_helicase)
PF08935 (VP4_2)
[Graphical View]

KEGG enzyme name
L-peptidase
(EC 3.4.22.46 )
nucleoside-triphosphatase
(EC 3.6.1.15 )
nucleoside triphosphate phosphohydrolase
(EC 3.6.1.15 )
nucleoside-5-triphosphate phosphohydrolase
(EC 3.6.1.15 )
nucleoside 5-triphosphatase
(EC 3.6.1.15 )
picornain 3C
(EC 3.4.22.28 )
picornavirus endopeptidase 3C
(EC 3.4.22.28 )
poliovirus protease 3C
(EC 3.4.22.28 )
rhinovirus protease 3C
(EC 3.4.22.28 )
foot-and-mouth protease 3C
(EC 3.4.22.28 )
poliovirus proteinase 3C
(EC 3.4.22.28 )
rhinovirus proteinase 3C
(EC 3.4.22.28 )
coxsackievirus 3C proteinase
(EC 3.4.22.28 )
foot-and-mouth-disease virus proteinase 3C
(EC 3.4.22.28 )
3C protease
(EC 3.4.22.28 )
3C proteinase
(EC 3.4.22.28 )
cysteine proteinase 3C
(EC 3.4.22.28 )
hepatitis A virus 3C proteinase
(EC 3.4.22.28 )
protease 3C
(EC 3.4.22.28 )
tomato ringspot nepovirus 3C-related protease
(EC 3.4.22.28 )
RNA-directed RNA polymerase
(EC 2.7.7.48 )
RNA nucleotidyltransferase (RNA-directed)
(EC 2.7.7.48 )
RNA nucleotidyltransferase (RNA-directed)
(EC 2.7.7.48 )
RNA-dependent ribonucleate nucleotidyltransferase
(EC 2.7.7.48 )
3D polymerase
(EC 2.7.7.48 )
PB1 proteins
(EC 2.7.7.48 )
PB2 proteins
(EC 2.7.7.48 )
phage f2 replicase
(EC 2.7.7.48 )
polymerase L
(EC 2.7.7.48 )
Q-beta replicase
(EC 2.7.7.48 )
phage f2 replicase
(EC 2.7.7.48 )
ribonucleic acid replicase
(EC 2.7.7.48 )
ribonucleic acid-dependent ribonucleate nucleotidyltransferase
(EC 2.7.7.48 )
ribonucleic acid-dependent ribonucleic acid polymerase
(EC 2.7.7.48 )
ribonucleic replicase
(EC 2.7.7.48 )
ribonucleic synthetase
(EC 2.7.7.48 )
RNA replicase
(EC 2.7.7.48 )
RNA synthetase
(EC 2.7.7.48 )
RNA transcriptase
(EC 2.7.7.48 )
RNA-dependent ribonucleate nucleotidyltransferase
(EC 2.7.7.48 )
RDRP
(EC 2.7.7.48 )
RNA-dependent RNA polymerase
(EC 2.7.7.48 )
RNA-dependent RNA replicase
(EC 2.7.7.48 )
transcriptase
(EC 2.7.7.48 )

UniprotKB: Accession Number Entry name Activity Subunit Subcellular location Cofactor
P03306 POLG_FMDV1 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-. NTP + H(2)O = NDP + phosphate. 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. Nucleoside triphosphate + RNA(n) = diphosphate + RNA(n+1). Protein VP2: Virion. Cytoplasm (Potential). Protein VP3: Virion. Cytoplasm (Potential). Protein VP1: Virion. Cytoplasm (Potential). Protein 2B: Cytoplasmic vesicle membrane, Peripheral membrane protein, Cytoplasmic side (Potential). Note=Probably localizes to the surface of intracellular membrane vesicles that are induced after virus infection as the site for viral RNA replication. These vesicles are derived from the endoplasmic reticulum (By similarity). Protein 2C: Cytoplasmic vesicle membrane, Peripheral membrane protein, Cytoplasmic side (Potential). Note=Probably localizes to the surface of intracellular membrane vesicles that are induced after virus infection as the site for viral RNA replication. These vesicles are derived from the endoplasmic reticulum (By similarity). Protein 3A: Cytoplasmic vesicle membrane, Peripheral membrane protein, Cytoplasmic side (Potential). Note=Probably localizes to the surface of intracellular membrane vesicles that are induced after virus infection as the site for viral RNA replication. These vesicles are derived from the endoplasmic reticulum (By similarity). Protein 3B-1: Virion (Potential). Protein 3B-2: Virion (Potential). Protein 3B-3: Virion (Potential). Picornain 3C: Cytoplasm (Potential). RNA-directed RNA polymerase 3D-POL: Cytoplasmic vesicle membrane, Peripheral membrane protein, Cytoplasmic side (Potential). Note=Probably localizes to the surface of intracellular membrane vesicles that are induced after virus infection as the site for viral RNA replication. These vesicles are derived from the endoplasmic reticulum (By similarity).

KEGG Pathways
Map code Pathways E.C.
MAP00730 Thiamine metabolism 3.6.1.15
MAP00230 Purine metabolism 3.6.1.15 2.7.7.48

Compound table
Substrates Products Intermediates
KEGG-id C00017 C00001 C00201 C00046 C00017 C00012 C00454 C00009 C00046 C00013
E.C. 3.4.22.46
3.4.22.28
3.4.22.46
3.4.22.28
3.6.1.15
3.6.1.15
2.7.7.48
2.7.7.48
3.4.22.46
3.4.22.28
3.4.22.46
3.4.22.28
3.6.1.15
3.6.1.15
2.7.7.48
2.7.7.48
Compound Protein H2O Nucleoside triphosphate RNA(n) Protein Peptide Nucleoside diphosphate Phosphate RNA(n+1) Diphosphate
Type peptide/protein H2O nucleotide nucleic acids peptide/protein peptide/protein nucleotide phosphate group/phosphate ion nucleic acids phosphate group/phosphate ion
ChEBI 15377
26078
29888
PubChem 22247451
962
1004
22486802
1023
21961011
1zba4 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1zbe4 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1zba2 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1zbe2 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1zba3 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1zbe3 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1zba1 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1zbe1 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound
2bhgA01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound
2bhgB01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound
2bhgA02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound
2bhgB02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound

Reference for Active-site residues
resource references E.C.
Swiss-prot;P03306 & literature [9]

Active-site residues
PDB Catalytic residues Cofactor-binding residues Modified residues Main-chain involved in catalysis Comment
1zba4 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain
1zbe4 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain
1zba2 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain
1zbe2 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain
1zba3 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain
1zbe3 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain
1zba1 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain
1zbe1 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain
2bhgA01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain HIS 46;ASP 84
2bhgB01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain HIS 46;ASP 84
2bhgA02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain GLY 161 mutant C163A
2bhgB02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain GLY 161 mutant C163A

References for Catalytic Mechanism
References Sections No. of steps in catalysis
[2]
p.110
[9]
p.11524

References
[1]
Resource
Comments
Medline ID
PubMed ID 3186696
Journal Proc Natl Acad Sci U S A
Year 1988
Volume 85
Pages 7872-6
Authors Bazan JF, Fletterick RJ
Title Viral cysteine proteases are homologous to the trypsin-like family of serine proteases: structural and functional implications.
Related PDB
Related UniProtKB
[2]
Resource
Comments
Medline ID
PubMed ID 2645167
Journal FEBS Lett
Year 1989
Volume 243
Pages 103-14
Authors Gorbalenya AE, Donchenko AP, Blinov VM, Koonin EV
Title Cysteine proteases of positive strand RNA viruses and chymotrypsin-like serine proteases. A distinct protein superfamily with a common structural fold.
Related PDB
Related UniProtKB
[3]
Resource
Comments
Medline ID
PubMed ID 8320292
Journal J Chem Inf Comput Sci
Year 1993
Volume 33
Pages 345-9
Authors Arad D, Kreisberg R, Shokhen M
Title Structural and mechanistic aspects of 3C proteases from the Picornavirus family.
Related PDB
Related UniProtKB
[4]
Resource
Comments
Medline ID
PubMed ID 8164744
Journal Nature
Year 1994
Volume 369
Pages 72-6
Authors Allaire M, Chernaia MM, Malcolm BA, James MN
Title Picornaviral 3C cysteine proteinases have a fold similar to chymotrypsin-like serine proteinases.
Related PDB
Related UniProtKB
[5]
Resource
Comments
Medline ID
PubMed ID 7491782
Journal Virology
Year 1995
Volume 213
Pages 581-9
Authors Grubman MJ, Zellner M, Bablanian G, Mason PW, Piccone ME
Title Identification of the active-site residues of the 3C proteinase of foot-and-mouth disease virus.
Related PDB
Related UniProtKB
[6]
Resource
Comments
Medline ID
PubMed ID 9060667
Journal J Virol
Year 1997
Volume 71
Pages 3062-8
Authors Gosert R, Dollenmaier G, Weitz M
Title Identification of active-site residues in protease 3C of hepatitis A virus by site-directed mutagenesis.
Related PDB
Related UniProtKB
[7]
Resource
Comments
Medline ID
PubMed ID 12036580
Journal Gene
Year 2002
Volume 289
Pages 19-29
Authors van Rensburg H, Haydon D, Joubert F, Bastos A, Heath L, Nel L
Title Genetic heterogeneity in the foot-and-mouth disease virus Leader and 3C proteinases.
Related PDB
Related UniProtKB
[8]
Resource
Comments
Medline ID
PubMed ID 12377789
Journal J Biol Chem
Year 2002
Volume 277
Pages 50564-72
Authors Phan J, Zdanov A, Evdokimov AG, Tropea JE, Peters HK 3rd, Kapust RB, Li M, Wlodawer A, Waugh DS
Title Structural basis for the substrate specificity of tobacco etch virus protease.
Related PDB
Related UniProtKB
[9]
Resource
Comments X-ray crystallography
Medline ID
PubMed ID 15654079
Journal J Biol Chem
Year 2005
Volume 280
Pages 11520-7
Authors Birtley JR, Knox SR, Jaulent AM, Brick P, Leatherbarrow RJ, Curry S
Title Crystal structure of foot-and-mouth disease virus 3C protease. New insights into catalytic mechanism and cleavage specificity.
Related PDB 2bhg
Related UniProtKB
[10]
Resource
Comments
Medline ID
PubMed ID 16288920
Journal J Mol Biol
Year 2005
Volume 354
Pages 854-71
Authors Yin J, Bergmann EM, Cherney MM, Lall MS, Jain RP, Vederas JC, James MN
Title Dual modes of modification of hepatitis A virus 3C protease by a serine-derived beta-lactone: selective crystallization and formation of a functional catalytic triad in the active site.
Related PDB
Related UniProtKB

Comments
The enzymes in this entry are parts of genome polyprotein from foot-and-mouth disease virus, which is composed of 4 coat proteins, 3 core proteins, 2 proteases (leader protease, picornain 3C), genome-linked proteins, 3D polymerase.
The tertiary structures for the 4 coat proteins (PDB; 1zba, 1zbe) and a protease (E.C. 3.4.22.28, PDB;2bhg) have been solved to date.
The enzyme (picornain 3C; EC 3.4.22.28) cleaves GLN/GLU-|-GLY/SER/THR bonds in its polyprotein. The catalytic domain strucutre for the peptidase has been solved so far. This protease belongs to the peptidase family-C3, to which picornain 3C from other picornaviruses (M00209, M00217) and picornain 2A (EC 3.4.22.29;M00217) belong.
The catalytic mechanism of this enzyme seems to be similar to that of trypsin (D00197 in EzCatDB), which is its homologous enzyme, although its catalytic site is composed of Cys/His/Asp and mainchain amide groups.

Created Updated
2006-07-11 2009-02-26