DB code: M00209

RLCP classification	1.13.30000.46 : Hydrolysis
CATH domain	2.60.120.20 : Jelly Rolls
	2.60.120.20 : Jelly Rolls
	-.-.-.- :
	-.-.-.- :
	-.-.-.- :
	2.40.10.10 : Thrombin, subunit H	Catalytic domain
	2.40.10.10 : Thrombin, subunit H	Catalytic domain
	-.-.-.- :
	4.10.880.10 : Poliovirus 3D polymerase; domain 1 (Nucleotidyltransferase)
	3.30.70.270 : Alpha-Beta Plaits
	1.20.960.20 : Mitochondrial Import Receptor Subunit Tom20; Chain A
E.C.	3.6.1.15 3.4.22.28 2.7.7.48
CSA
M-CSA
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 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 Plaits	M00206 M00019 M00135 M00146 M00166

Uniprot Enzyme Name
UniprotKB	Protein name	Synonyms	Contains	RefSeq	Pfam
P08617	Genome polyprotein	None	Protein 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	NP_041007.1 (Protein) NC_001489.1 (DNA/RNA sequence) NP_041008.1 (Protein) NC_001489.1 (DNA/RNA sequence)	PF12944 (DUF3840) PF00548 (Peptidase_C3) PF00680 (RdRP_1) PF00073 (Rhv) PF00910 (RNA_helicase) [Graphical View]

KEGG enzyme name

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
P08617	POLG_HAVHM	Nucleoside 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.	3AB precursor is a homodimer. 3AB precursor interacts with 3CD precursor. Protein 3ABC interacts with human MAVS.	Protein 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.

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

Compound table
						Substrates				Products						Intermediates
KEGG-id						C00201	C00017	C00001	C00046	C00454	C00009	C00017	C00012	C00046	C00013	I00153	I00154	I00155
E.C.						3.6.1.15 2.7.7.48	3.4.22.28	3.6.1.15 3.4.22.28	2.7.7.48	3.6.1.15	3.6.1.15	3.4.22.28	3.4.22.28	2.7.7.48	2.7.7.48	3.4.22.28	3.4.22.28	3.4.22.28
Compound						Nucleoside triphosphate	Protein	H2O	RNA(n)	Nucleoside diphosphate	Phosphate	Protein	Peptide	RNA(n+1)	Diphosphate	Peptidyl-Cys-tetrahedral-intermediate (with previous peptide)	Acyl-enzyme(Peptidyl-Cys-acyl group)	Peptidyl-Cys-tetrahedral-intermediate
Type						nucleotide	peptide/protein	H2O	nucleic acids	nucleotide	phosphate group/phosphate ion	peptide/protein	peptide/protein	nucleic acids	phosphate group/phosphate ion
ChEBI								15377 15377			26078 26078				29888 29888
PubChem								22247451 962 22247451 962			1004 22486802 1004 22486802				1023 21961011 1023 21961011
1havA01						Unbound	Unbound		Unbound	Unbound	Unbound	Unbound	Unbound	Unbound	Unbound	Unbound	Unbound	Unbound
1havB01						Unbound	Unbound		Unbound	Unbound	Unbound	Unbound	Unbound	Unbound	Unbound	Unbound	Unbound	Unbound
1qa7A01						Unbound	Unbound		Unbound	Unbound	Unbound	Unbound	Unbound	Unbound	Unbound	Unbound	Unbound	Unbound
1qa7B01						Unbound	Unbound		Unbound	Unbound	Unbound	Unbound	Unbound	Unbound	Unbound	Unbound	Unbound	Unbound
1qa7C01						Unbound	Unbound		Unbound	Unbound	Unbound	Unbound	Unbound	Unbound	Unbound	Unbound	Unbound	Unbound
1qa7D01						Unbound	Unbound		Unbound	Unbound	Unbound	Unbound	Unbound	Unbound	Unbound	Unbound	Unbound	Unbound
1havA02						Unbound	Unbound		Unbound	Unbound	Unbound	Unbound	Unbound	Unbound	Unbound	Unbound	Unbound	Unbound
1havB02						Unbound	Unbound		Unbound	Unbound	Unbound	Unbound	Unbound	Unbound	Unbound	Unbound	Unbound	Unbound
1qa7A02						Unbound	Unbound		Unbound	Unbound	Unbound	Unbound	Unbound	Unbound	Unbound	Unbound	Intermediate-analogue:IVF	Unbound
1qa7B02						Unbound	Unbound		Unbound	Unbound	Unbound	Unbound	Unbound	Unbound	Unbound	Unbound	Intermediate-analogue:IVF	Unbound
1qa7C02						Unbound	Unbound		Unbound	Unbound	Unbound	Unbound	Unbound	Unbound	Unbound	Unbound	Intermediate-analogue:IVF	Unbound
1qa7D02						Unbound	Unbound		Unbound	Unbound	Unbound	Unbound	Unbound	Unbound	Unbound	Unbound	Intermediate-analogue:IVF	Unbound

Reference for Active-site residues
resource	references	E.C.
PDB;1hav & literature [7]

Active-site residues
PDB						Catalytic residues	Cofactor-binding residues	Modified residues	Main-chain involved in catalysis	Comment
1havA01						HIS 44				mutant C24S
1havB01						HIS 44				mutant C24S
1qa7A01						HIS 44
1qa7B01						HIS 44
1qa7C01						HIS 44
1qa7D01						HIS 44
1havA02						TYR 143;CYS 172			MET 171;CYS 172
1havB02						TYR 143;OCS 172		OCS 172(Sulfonic acid)	MET 171;OCS 172
1qa7A02						TYR 143;CYS 172			MET 171;CYS 172
1qa7B02						TYR 143;CYS 172			MET 171;CYS 172
1qa7C02						TYR 143;CYS 172			MET 171;CYS 172
1qa7D02						TYR 143;CYS 172			MET 171;CYS 172

References for Catalytic Mechanism
References	Sections	No. of steps in catalysis
[4]	p.75
[7]	p.2440-2442
[9]	p.159

References
[1]
Resource
Comments
Medline ID
PubMed ID	8254682
Journal	J Mol Biol
Year	1993
Volume	234
Pages	890-3
Authors	Chernaia MM, Malcolm BA, Allaire M, James MN
Title	Hepatitis A virus 3C proteinase: some properties, crystallization and preliminary crystallographic characterization.
Related PDB
Related UniProtKB
[2]
Resource
Comments
Medline ID
PubMed ID	8071130
Journal	J Antibiot (Tokyo)
Year	1994
Volume	47
Pages	836-9
Authors	Kadam S, Poddig J, Humphrey P, Karwowski J, Jackson M, Tennent S, Fung L, Hochlowski J, Rasmussen R, McAlpine J
Title	Citrinin hydrate and radicinin: human rhinovirus 3C-protease inhibitors discovered in a target-directed microbial screen.
Related PDB
Related UniProtKB
[3]
Resource
Comments
Medline ID
PubMed ID	7664075
Journal	Nat Struct Biol
Year	1994
Volume	1
Pages	505-6
Authors	Allaire M, James M
Title	Deduction of the 3C proteinases' fold.
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	7794931
Journal	Biochemistry
Year	1995
Volume	34
Pages	8172-9
Authors	Malcolm BA, Lowe C, Shechosky S, McKay RT, Yang CC, Shah VJ, Simon RJ, Vederas JC, Santi DV
Title	Peptide aldehyde inhibitors of hepatitis A virus 3C proteinase.
Related PDB
Related UniProtKB
[6]
Resource
Comments
Medline ID
PubMed ID	9367789
Journal	J Mol Biol
Year	1997
Volume	273
Pages	1032-47
Authors	Mosimann SC, Cherney MM, Sia S, Plotch S, James MN
Title	Refined X-ray crystallographic structure of the poliovirus 3C gene product.
Related PDB
Related UniProtKB
[7]
Resource
Comments	X-ray crystallography
Medline ID
PubMed ID	9032381
Journal	J Virol
Year	1997
Volume	71
Pages	2436-48
Authors	Bergmann EM, Mosimann SC, Chernaia MM, Malcolm BA, James MN
Title	The refined crystal structure of the 3C gene product from hepatitis A virus: specific proteinase activity and RNA recognition.
Related PDB	1hav
Related UniProtKB
[8]
Resource
Comments
Medline ID
PubMed ID	10353640
Journal	Bioorg Med Chem
Year	1999
Volume	7
Pages	607-19
Authors	Huang Y, Malcolm BA, Vederas JC
Title	Synthesis and testing of azaglutamine derivatives as inhibitors of hepatitis A virus (HAV) 3C proteinase.
Related PDB
Related UniProtKB
[9]
Resource
Comments
Medline ID
PubMed ID	10603326
Journal	Virology
Year	1999
Volume	265
Pages	153-63
Authors	Bergmann EM, Cherney MM, Mckendrick J, Frormann S, Luo C, Malcolm BA, Vederas JC, James MN
Title	Crystal structure of an inhibitor complex of the 3C proteinase from hepatitis A virus (HAV) and implications for the polyprotein processing in HAV.
Related PDB
Related UniProtKB
[10]
Resource
Comments
Medline ID
PubMed ID	10507325
Journal	Virus Res
Year	1999
Volume	62
Pages	159-68
Authors	Seipelt J, Guarne A, Bergmann E, James M, Sommergruber W, Fita I, Skern T
Title	The structures of picornaviral proteinases.
Related PDB
Related UniProtKB
[11]
Resource
Comments
Medline ID
PubMed ID	11256814
Journal	J Biomol NMR
Year	2001
Volume	19
Pages	187-8
Authors	Bjorndahl TC, Watson MS, Slupsky CM, Spyracopoulos L, Sykes BD, Wishart DS
Title	Complete 1H, 13C and 15N backbone assignments for the hepatitis A virus 3C protease.
Related PDB
Related UniProtKB

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.

Created	Updated
2003-07-22	2012-10-22