EzCatDB: M00209
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DB codeM00209
RLCP classification1.13.30000.46 : Hydrolysis
CATH domainDomain 12.60.120.20 : Jelly Rolls
Domain 22.60.120.20 : Jelly Rolls
Domain 3-.-.-.-
Domain 4-.-.-.-
Domain 5-.-.-.-
Domain 62.40.10.10 : Thrombin, subunit HCatalytic domain
Domain 72.40.10.10 : Thrombin, subunit HCatalytic domain
Domain 8-.-.-.-
Domain 94.10.880.10 : Poliovirus 3D polymerase; domain 1 (Nucleotidyltransferase)
Domain 103.30.70.270 : Alpha-Beta Plaits
Domain 111.20.960.20 : Mitochondrial Import Receptor Subunit Tom20; Chain A
E.C.3.6.1.15,3.4.22.28,2.7.7.48

CATH domainRelated DB codes (homologues)
2.40.10.10 : Thrombin, subunit HM00139,D00214,M00167,D00426,M00133,D00428,D00429,D00430,D00431,D00432,D00433,D00434,D00435,M00227,D00194,D00197,D00211,D00212,D00216,M00212,D00224,D00497,M00217,M00216,D00528,D00848,D00850,D00851,D00852,D00855,M00152,M00155,M00157,M00181,M00315,M00316,M00317,M00348,M00349,T00074,T00410,T00411
3.30.70.270 : Alpha-Beta PlaitsM00206,M00019,M00135,M00146,M00166

Enzyme Name
UniProtKBKEGG

P08617
Protein nameGenome polyproteinnucleoside-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)

SynonymsNone
ContainsProtein VP0 VP4-VP2
Protein VP4 P1A Virion protein 4
Protein VP2 P1B Virion protein 2
Protein VP3 P1C Virion protein 3
Protein VP1-2A PX
Protein VP1 P1D Virion protein 1
Protein 2A
(P2A)
Protein 2BC
Protein 2B
(P2B)
Protein 2C
(P2C)
   EC 3.6.1.15
Protein 3ABCD
(P3)
Protein 3ABC
Protein 3AB
Protein 3A
(P3A)
Protein 3B
(P3B)
VPg
Protein 3CD
Protease 3C
(P3C)
   EC 3.4.22.28
Picornain 3C
RNA-directed RNA polymerase 3D-POL
(P3D-POL)
   EC 2.7.7.48
RefSeqNP_041007.1 (Protein)
NC_001489.1 (DNA/RNA sequence)
NP_041008.1 (Protein)
PfamPF12944 (DUF3840)
PF00548 (Peptidase_C3)
PF00680 (RdRP_1)
PF00073 (Rhv)
PF00910 (RNA_helicase)
[Graphical view]

KEGG pathways
MAP codePathwaysE.C.
MAP00230Purine metabolism3.6.1.15,2.7.7.48
MAP00730Thiamine metabolism3.6.1.15

UniProtKB:Accession NumberP08617
Entry namePOLG_HAVHM
ActivityNucleoside triphosphate + RNA(n) = diphosphate + RNA(n+1).,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.,NTP + H(2)O = NDP + phosphate.
Subunit3AB precursor is a homodimer. 3AB precursor interacts with 3CD precursor. Protein 3ABC interacts with human MAVS.
Subcellular locationProtein VP2: Virion. Cytoplasm (Potential).,Protein VP3: Virion. Cytoplasm (Potential).,Protein VP1: Virion. Cytoplasm (Potential).,Protein VP1-2A: 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.,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. May associate with membranes through a N- terminal amphipathic helix.,Protein 3ABC: Cytoplasmic vesicle membrane, Peripheral membrane protein, Cytoplasmic side (Potential). Mitochondrion outer 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.,Protein 3AB: 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.,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.,Protein 3B: Virion (Potential).,Picornain 3C: Cytoplasm (Potential).,RNA-directed RNA polymerase 3D-POL: Cytoplasmic vesicle membrane, Peripheral membrane protein, Cytoplasmic side (Potential). Note=Interacts with membranes in a complex with viral protein 3AB. 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.
Cofactor

Compound table: links to PDB-related databases & PoSSuM

SubstratesProductsintermediates
KEGG-idC00201C00017C00001C00046C00454C00009C00017C00012C00046C00013I00153I00154I00155
E.C.3.6.1.15,2.7.7.483.4.22.283.6.1.15,3.4.22.282.7.7.483.6.1.153.6.1.153.4.22.283.4.22.282.7.7.482.7.7.483.4.22.283.4.22.283.4.22.28
CompoundNucleoside triphosphateProteinH2ORNA(n)Nucleoside diphosphatePhosphateProteinPeptideRNA(n+1)DiphosphatePeptidyl-Cys-tetrahedral-intermediate (with previous peptide)Acyl-enzyme(Peptidyl-Cys-acyl group)Peptidyl-Cys-tetrahedral-intermediate
Typenucleotidepeptide/proteinH2Onucleic acidsnucleotidephosphate group/phosphate ionpeptide/proteinpeptide/proteinnucleic acidsphosphate group/phosphate ion


ChEBI

15377


26078



29888



PubChem

962
22247451


22486802
1004



21961011
1023



                     
1havA01UnboundUnbound UnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
1havB01UnboundUnbound UnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
1qa7A01UnboundUnbound UnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
1qa7B01UnboundUnbound UnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
1qa7C01UnboundUnbound UnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
1qa7D01UnboundUnbound UnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
1havA02UnboundUnbound UnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
1havB02UnboundUnbound UnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
1qa7A02UnboundUnbound UnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundIntermediate-analogue:IVFUnbound
1qa7B02UnboundUnbound UnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundIntermediate-analogue:IVFUnbound
1qa7C02UnboundUnbound UnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundIntermediate-analogue:IVFUnbound
1qa7D02UnboundUnbound UnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundIntermediate-analogue:IVFUnbound

Active-site residues
resource
PDB;1hav & literature [7]
pdbCatalytic residuesModified residuesMain-chain involved in catalysiscomment
            
1havA01HIS 44
 
 
mutant C24S
1havB01HIS 44
 
 
mutant C24S
1qa7A01HIS 44
 
 
 
1qa7B01HIS 44
 
 
 
1qa7C01HIS 44
 
 
 
1qa7D01HIS 44
 
 
 
1havA02TYR 143;CYS 172
                      
MET 171;CYS 172
 
1havB02TYR 143;OCS 172
OCS 172(Sulfonic acid)
MET 171;OCS 172
 
1qa7A02TYR 143;CYS 172
                      
MET 171;CYS 172
 
1qa7B02TYR 143;CYS 172
                      
MET 171;CYS 172
 
1qa7C02TYR 143;CYS 172
                      
MET 171;CYS 172
 
1qa7D02TYR 143;CYS 172
                      
MET 171;CYS 172
 

References for Catalytic Mechanism
ReferencesSectionsNo. of steps in catalysis
[4]p.75
[7]p.2440-2442
[9]p.159

references
[1]
PubMed ID8254682
JournalJ Mol Biol
Year1993
Volume234
Pages890-3
AuthorsChernaia MM, Malcolm BA, Allaire M, James MN
TitleHepatitis A virus 3C proteinase: some properties, crystallization and preliminary crystallographic characterization.
[2]
PubMed ID8071130
JournalJ Antibiot (Tokyo)
Year1994
Volume47
Pages836-9
AuthorsKadam S, Poddig J, Humphrey P, Karwowski J, Jackson M, Tennent S, Fung L, Hochlowski J, Rasmussen R, McAlpine J
TitleCitrinin hydrate and radicinin: human rhinovirus 3C-protease inhibitors discovered in a target-directed microbial screen.
[3]
PubMed ID7664075
JournalNat Struct Biol
Year1994
Volume1
Pages505-6
AuthorsAllaire M, James M
TitleDeduction of the 3C proteinases' fold.
[4]
PubMed ID8164744
JournalNature
Year1994
Volume369
Pages72-6
AuthorsAllaire M, Chernaia MM, Malcolm BA, James MN
TitlePicornaviral 3C cysteine proteinases have a fold similar to chymotrypsin-like serine proteinases.
[5]
PubMed ID7794931
JournalBiochemistry
Year1995
Volume34
Pages8172-9
AuthorsMalcolm BA, Lowe C, Shechosky S, McKay RT, Yang CC, Shah VJ, Simon RJ, Vederas JC, Santi DV
TitlePeptide aldehyde inhibitors of hepatitis A virus 3C proteinase.
[6]
PubMed ID9367789
JournalJ Mol Biol
Year1997
Volume273
Pages1032-47
AuthorsMosimann SC, Cherney MM, Sia S, Plotch S, James MN
TitleRefined X-ray crystallographic structure of the poliovirus 3C gene product.
[7]
CommentsX-ray crystallography
PubMed ID9032381
JournalJ Virol
Year1997
Volume71
Pages2436-48
AuthorsBergmann EM, Mosimann SC, Chernaia MM, Malcolm BA, James MN
TitleThe refined crystal structure of the 3C gene product from hepatitis A virus: specific proteinase activity and RNA recognition.
Related PDB1hav
[8]
PubMed ID10353640
JournalBioorg Med Chem
Year1999
Volume7
Pages607-19
AuthorsHuang Y, Malcolm BA, Vederas JC
TitleSynthesis and testing of azaglutamine derivatives as inhibitors of hepatitis A virus (HAV) 3C proteinase.
[9]
PubMed ID10603326
JournalVirology
Year1999
Volume265
Pages153-63
AuthorsBergmann EM, Cherney MM, Mckendrick J, Frormann S, Luo C, Malcolm BA, Vederas JC, James MN
TitleCrystal structure of an inhibitor complex of the 3C proteinase from hepatitis A virus (HAV) and implications for the polyprotein processing in HAV.
[10]
PubMed ID10507325
JournalVirus Res
Year1999
Volume62
Pages159-68
AuthorsSeipelt J, Guarne A, Bergmann E, James M, Sommergruber W, Fita I, Skern T
TitleThe structures of picornaviral proteinases.
[11]
PubMed ID11256814
JournalJ Biomol NMR
Year2001
Volume19
Pages187-8
AuthorsBjorndahl TC, Watson MS, Slupsky CM, Spyracopoulos L, Sykes BD, Wishart DS
TitleComplete 1H, 13C and 15N backbone assignments for the hepatitis A virus 3C protease.

comments
The virus proteins (Swiss-prot;P08617, P26582) are composed of four coat proteins, three core proteins, P2A, P2B and P2C (E.C. 3.6.1.15), and three probable proteins, P3A, P3B and P3C, and RNA-directed polymerase 3D (E.C. 2.7.7.48). However, the structures (PDB; 1hav & 1qa7) correspond to the P3C, which seems to be cysteine protease.
This protease belongs to the peptidase family-C3.
According to the literature [7] & [9], Cys172 acts as a nucleophile, whilst His44 serve as a general acid-base. The nucleophilic cysteine and the acid-base histidine form a thiolate-imidazolium ion pair. Moreover, this enzyme has got the electrophilic oxyanion hole, made up by the mainchain of residues 169-172, as observed in chymotrypsin.
Furthermore, the sidechain of Tyr143 is close to a water, which is hydrogen-bonded to His44, and to His44. This residue is considered to be negatively charged (see [7]). Thus, Tyr143 might stabilize a positive charge on the imidazole of His44, to maintain the protonation state of His44.

createdupdated
2003-07-222012-10-22


Copyright: Nozomi Nagano, JST & CBRC-AIST
Funded by PRESTO/Japan Science and Technology Corporation (JST) (December 2001 - November 2004)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2005 - March 2006)
Funded by Grant-in-Aid for Scientific Research (B)/Japan Society for the Promotion of Science (JSPS) (April 2005 - March 2008)
Funded by BIRD/Japan Science and Technology Corporation (JST) (September 2005 - September 2008)
Funded by BIRD/Japan Science and Technology Corporation (JST) (October 2007 - September 2010)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2011 - March 2012)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2012 - March 2013)
Supported by the commission for the Development of Artificial Gene Synthesis Technology for Creating Innovative Biomaterial from the Ministry of Economy, Trade and Industry (METI) (October 2012 - )
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