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Information on EC 3.4.22.66 - calicivirin
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- 3.4.22.66
- coronavirus
- sars-cov-2
- covid-19
- polyproteins
- pandemic
-
repurposing
-
outbreak
- plpro
-
3-chymotrypsin-like
-
papain-like
-
rna-dependent
- remdesivir
- ace2
- mers-cov
-
ramaswamy
-
replicase
-
nonstructural
-
sarma
-
wuhan
- lopinavir
-
admet
-
anti-sars-cov-2
-
mhv-a59
-
genogroups
- picornavirus
- caliciviruses
- medicine
-
anti-sars
-
norwalk
-
anti-covid-19
- betacoronavirus
-
sars-coronavirus
-
anti-coronavirus
-
trans-cleavage
- drug development
- pp1ab
- caliciviridae
The enzyme appears in viruses and cellular organisms
Reaction Schemes
endopeptidase with a preference for cleavage when the P1 position is occupied by Glu-/- and the P1' position is occupied by Gly-/-
Synonyms
3clpro, 3c-like protease, 3c-like proteinase, 3c-like cysteine protease, 3cl pro, nv protease, nv 3clpro, virus-encoded 3c-like proteinase, calicivirus protease, 3c-like viral protease, 
more
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
3C protease
3C-like cysteine protease
3C-like protease
3C-like proteinase
3C-like viral protease
-
-
-
-
3cLpro
3Cpro
C37.001
-
-
-
-
calicivirus protease
NoV 3CLpro
NV 3CLpro
Southampton virus 3C-like protease
-
-
-
-
3Cpro
-
-
-
-
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
endopeptidase with a preference for cleavage when the P1 position is occupied by Glu-/- and the P1' position is occupied by Gly-/-
-
-
-
-
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
hydrolysis of peptide bond
-
-
-
-
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CAS REGISTRY NUMBER
COMMENTARY
218925-73-6
-
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
Glu-Thr-Thr-Leu-Glu-Gly-Gly-Asp
Glu-Thr-Thr-Leu-Glu + Gly-Gly-Asp
-
model of an oligopeptide bound to CVP
-
-
?
ORF1 polyprotein + H2O
precursor comprised of both the proteinase and polymerase + mature polymerase
ORF1 polyprotein + H2O
six nonstructural proteins for replication
-
-
-
?
Poly(A)-binding protein + H2O
?
cleavage separates the C-terminal domain of the substrate that binds translation factors eIF4B and eRF3 from the N-terminal RNA-binding domain
-
-
?
Southampton viral polyprotein precursor p113 + H2O
p48 N-terminal + p41 helicase + 22000 Da 3A-like protein + 16000 Da Vpg + 19000 Da 3C-like viral protease + 57000 Da 3D polymerase
-
cleavage sites are Q399-/-G400, Q762-/-G763, E961-/-G962, E1099-/-A1100 and E1280-/-G1281
-
?
Dabcyl-KTSAVLQSGFRKME-EDANS + H2O
Dabcyl-KTSAVLQ + SGFRKME-EDANS
-
-
-
-
?
Dabcyl-KTSAVLQSGFRKME-EDANS + H2O
Dabcyl-KTSAVLQ + SGFRKME-EDANS
-
-
-
?
Dabcyl-KTSAVLQSGFRKME-EDANS + H2O
Dabcyl-KTSAVLQ + SGFRKME-EDANS
-
-
-
?
Edans-DFHLQGP-Dabcyl + H2O
Edans-DFHLQ + GP-Dabcyl
-
-
-
-
?
Edans-DFHLQGP-Dabcyl + H2O
Edans-DFHLQ + GP-Dabcyl
truncated substrate
-
-
?
F4 NS6-7 protein + H2O
?
-
strain F4 protein containing protease and RNA-dependent RNA-polymerase region
-
-
?
F4 NS6-7 protein + H2O
?
-
strain F4 protein containing protease and RNA-dependent RNA-polymerase region
-
-
?
ORF1 polyprotein + H2O
precursor comprised of both the proteinase and polymerase + mature polymerase
-
-
-
-
?
ORF1 polyprotein + H2O
precursor comprised of both the proteinase and polymerase + mature polymerase
-
-
-
-
?
poly(A)-binding protein
?
-
cleavage separates the C-terminal domain of the substrate that binds translation factors eIF4B and eRF3 from the N-terminal RNA-binding domain
-
-
?
poly(A)-binding protein
?
-
cleavage separates the C-terminal domain of the substrate that binds translation factors eIF4B and eRF3 from the N-terminal RNA-binding domain
-
-
?
poly(A)-binding protein
?
-
cleavage separates the C-terminal domain of the substrate that binds translation factors eIF4B and eRF3 from the N-terminal RNA-binding domain
-
-
?
additional information
?
-
-
four amino acid residues are essential to protease activities: H39, E60, C122, and H137. These amino acids are involved in the formation of a conserved catalytic surface
-
-
?
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NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
Southampton viral polyprotein precursor p113 + H2O
p48 N-terminal + p41 helicase + 22000 Da 3A-like protein + 16000 Da Vpg + 19000 Da 3C-like viral protease + 57000 Da 3D polymerase
-
cleavage sites are Q399-/-G400, Q762-/-G763, E961-/-G962, E1099-/-A1100 and E1280-/-G1281
-
?
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INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
(2S)-2-([N-[(benzyloxy)carbonyl]-L-leucyl]amino)-1-hydroxy-3-(2-oxopyrrolidin-3-yl)propane-1-sulfonic acid
1,6-di(propan-2-yl)-N-(4-[[4-(prop-2-en-1-yl)-5-sulfanylidene-4,5-dihydro-1H-1,2,4-triazol-3-yl]methyl]-1,3-thiazol-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide
-
compound is predicted to bind to feline calicivirus proteases in a mode similar to that of the authentic substrate, and has the ability to inhibit viral protease activity in vitro and in the cells, and to suppress viral replication in FCV-infected cells. The authentic substrate and anti-FCV compound share a highly conserved binding site
4-(2-aminoethyl)-benzene-sulfonyl fluoride
irreversible inhibition, soluble stable nontoxic alternative to phenylmethylsulfonyl fluoride
benzyl ((3S,6S,9S,Z)-6-(cyclohexylmethyl)-9-formyl-4,7,12-trioxo-11H-5,8,13-triaza-1(4,1)-triazolacyclohexadecaphane-3-yl)carbamate
-
benzyl ((3S,6S,9S,Z)-9-formyl-6-isobutyl-4,7,12-trioxo-11H-5,8,13-triaza-1(4,1)-triazolacyclohexadecaphane-3-yl)carbamate
-
benzyl ((8S,11S,14S,Z)-11-(cyclohexylmethyl)-8-formyl-5,10,13-trioxo-11H-4,9,12-triaza-1(1,4)-triazolacyclopentadecaphane-14-yl)carbamate
-
benzyl [(2S)-1-[[(2S)-3-methyl-1-oxo-1-([(2S)-1-oxo-3-[(1S)-2-oxocyclopentyl]propan-2-yl]amino)butan-2-yl]amino]-3-(naphthalen-1-yl)-1-oxopropan-2-yl]carbamate
N2-[(benzyloxy)carbonyl]-N-[(2S)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]-1-(sulfinooxy)propan-2-yl]-L-valinamide
N2-[(benzyloxy)carbonyl]-N-[(2S)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)-4-(propan-2-ylamino)butan-2-yl]-L-leucinamide
(2S)-2-([N-[(benzyloxy)carbonyl]-L-leucyl]amino)-1-hydroxy-3-(2-oxopyrrolidin-3-yl)propane-1-sulfonic acid
-
-
(2S)-2-([N-[(benzyloxy)carbonyl]-L-leucyl]amino)-1-hydroxy-3-(2-oxopyrrolidin-3-yl)propane-1-sulfonic acid
-
-
(2S)-2-([N-[(benzyloxy)carbonyl]-L-leucyl]amino)-1-hydroxy-3-(2-oxopyrrolidin-3-yl)propane-1-sulfonic acid
-
-
(2S)-2-([N-[(benzyloxy)carbonyl]-L-leucyl]amino)-1-hydroxy-3-(2-oxopyrrolidin-3-yl)propane-1-sulfonic acid
-
(2S)-2-([N-[(benzyloxy)carbonyl]-L-leucyl]amino)-1-hydroxy-3-(2-oxopyrrolidin-3-yl)propane-1-sulfonic acid
-
-
(2S)-2-([N-[(benzyloxy)carbonyl]-L-leucyl]amino)-1-hydroxy-3-(2-oxopyrrolidin-3-yl)propane-1-sulfonic acid
-
benzyl [(2S)-1-[[(2S)-3-methyl-1-oxo-1-([(2S)-1-oxo-3-[(1S)-2-oxocyclopentyl]propan-2-yl]amino)butan-2-yl]amino]-3-(naphthalen-1-yl)-1-oxopropan-2-yl]carbamate
-
tripeptidyl compound, potent antiviral activities against both feline coronavirus strain WSU-79-1146 and feline calicivirus strain Urbana. Treatment of coronavirus-infected mice with the compound at 100 mg/kg results in a significant reduction in liver virus titers
benzyl [(2S)-1-[[(2S)-3-methyl-1-oxo-1-([(2S)-1-oxo-3-[(1S)-2-oxocyclopentyl]propan-2-yl]amino)butan-2-yl]amino]-3-(naphthalen-1-yl)-1-oxopropan-2-yl]carbamate
-
tripeptidyl compound, potent antiviral activities against both feline coronavirus strain WSU-79-1146 and feline calicivirus strain Urbana. Treatment of coronavirus-infected mice with the compound at 100 mg/kg results in a significant reduction in liver virus titers
N2-[(benzyloxy)carbonyl]-N-[(2S)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]-1-(sulfinooxy)propan-2-yl]-L-valinamide
-
dipeptidyl compound, statistically significant reduction in the viral load in the liver of virus-infected mice is consistently observed
N2-[(benzyloxy)carbonyl]-N-[(2S)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]-1-(sulfinooxy)propan-2-yl]-L-valinamide
-
dipeptidyl compound, statistically significant reduction in the viral load in the liver of virus-infected mice is consistently observed
N2-[(benzyloxy)carbonyl]-N-[(2S)-1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl]-L-leucinamide
-
-
N2-[(benzyloxy)carbonyl]-N-[(2S)-1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl]-L-leucinamide
-
-
N2-[(benzyloxy)carbonyl]-N-[(2S)-1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl]-L-leucinamide
-
-
N2-[(benzyloxy)carbonyl]-N-[(2S)-1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl]-L-leucinamide
-
N2-[(benzyloxy)carbonyl]-N-[(2S)-1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl]-L-leucinamide
-
-
N2-[(benzyloxy)carbonyl]-N-[(2S)-1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl]-L-leucinamide
-
N2-[(benzyloxy)carbonyl]-N-[(2S)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)-4-(propan-2-ylamino)butan-2-yl]-L-leucinamide
-
-
N2-[(benzyloxy)carbonyl]-N-[(2S)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)-4-(propan-2-ylamino)butan-2-yl]-L-leucinamide
-
-
N2-[(benzyloxy)carbonyl]-N-[(2S)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)-4-(propan-2-ylamino)butan-2-yl]-L-leucinamide
-
-
N2-[(benzyloxy)carbonyl]-N-[(2S)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)-4-(propan-2-ylamino)butan-2-yl]-L-leucinamide
-
N2-[(benzyloxy)carbonyl]-N-[(2S)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)-4-(propan-2-ylamino)butan-2-yl]-L-leucinamide
-
-
N2-[(benzyloxy)carbonyl]-N-[(2S)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)-4-(propan-2-ylamino)butan-2-yl]-L-leucinamide
-
additional information
-
not inhibited by Mg2+, Ca2+, 0.01 mM iodoacetate nor 0.01 mM iodoacetamide
-
additional information
-
efficiency of inhibitors in inhibition of virus replication, quantitative realtime PCR expression analysis, overview
-
additional information
-
efficiency of inhibitors in inhibition of virus replication, quantitative realtime PCR expression analysis, overview
-
additional information
-
efficiency of inhibitors in inhibition of virus replication, quantitative realtime PCR expression analysis, overview
-
additional information
efficiency of inhibitors in inhibition of virus replication, quantitative realtime PCR expression analysis, overview
-
additional information
-
efficiency of inhibitors in inhibition of virus replication, quantitative realtime PCR expression analysis, overview
-
additional information
-
efficiency of inhibitors in inhibition of virus replication, quantitative realtime PCR expression analysis, overview
-
additional information
efficiency of inhibitors in inhibition of virus replication, quantitative realtime PCR expression analysis, overview
-
additional information
-
efficiency of inhibitors in inhibition of virus replication, quantitative realtime PCR expression analysis, overview
-
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.00049 - 0.05
(2S)-2-([N-[(benzyloxy)carbonyl]-L-leucyl]amino)-1-hydroxy-3-(2-oxopyrrolidin-3-yl)propane-1-sulfonic acid
0.0016
benzyl ((3S,6S,9S,Z)-6-(cyclohexylmethyl)-9-formyl-4,7,12-trioxo-11H-5,8,13-triaza-1(4,1)-triazolacyclohexadecaphane-3-yl)carbamate
Norwalk virus
pH 8.0, 37°C
0.0024
benzyl ((3S,6S,9S,Z)-9-formyl-6-isobutyl-4,7,12-trioxo-11H-5,8,13-triaza-1(4,1)-triazolacyclohexadecaphane-3-yl)carbamate
Norwalk virus
pH 8.0, 37°C
0.0029
benzyl ((8S,11S,14S,Z)-11-(cyclohexylmethyl)-8-formyl-5,10,13-trioxo-11H-4,9,12-triaza-1(1,4)-triazolacyclopentadecaphane-14-yl)carbamate
Norwalk virus
pH 8.0, 37°C
0.00061 - 0.05
N2-[(benzyloxy)carbonyl]-N-[(2S)-1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl]-L-leucinamide
0.00055 - 0.0426
N2-[(benzyloxy)carbonyl]-N-[(2S)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)-4-(propan-2-ylamino)butan-2-yl]-L-leucinamide
0.00049
(2S)-2-([N-[(benzyloxy)carbonyl]-L-leucyl]amino)-1-hydroxy-3-(2-oxopyrrolidin-3-yl)propane-1-sulfonic acid
Norwalk virus
pH 8.0, 37°C, recombinant enzyme
0.00082
(2S)-2-([N-[(benzyloxy)carbonyl]-L-leucyl]amino)-1-hydroxy-3-(2-oxopyrrolidin-3-yl)propane-1-sulfonic acid
Transmissible gastroenteritis virus
pH 6.0, 37°C, recombinant enzyme
0.00096
(2S)-2-([N-[(benzyloxy)carbonyl]-L-leucyl]amino)-1-hydroxy-3-(2-oxopyrrolidin-3-yl)propane-1-sulfonic acid
Human calicivirus Hu/NLV/GII/MD145-12/1987/US
-
pH 8.0, 37°C, recombinant enzyme
0.00116
(2S)-2-([N-[(benzyloxy)carbonyl]-L-leucyl]amino)-1-hydroxy-3-(2-oxopyrrolidin-3-yl)propane-1-sulfonic acid
Foot-and-mouth disease virus
-
pH 8.0, 37°C, recombinant enzyme
0.00435
(2S)-2-([N-[(benzyloxy)carbonyl]-L-leucyl]amino)-1-hydroxy-3-(2-oxopyrrolidin-3-yl)propane-1-sulfonic acid
Severe acute respiratory syndrome-related coronavirus
-
pH 6.0, 37°C, recombinant enzyme
0.05
(2S)-2-([N-[(benzyloxy)carbonyl]-L-leucyl]amino)-1-hydroxy-3-(2-oxopyrrolidin-3-yl)propane-1-sulfonic acid
Hepatovirus A
-
above, pH 8.0, 37°C, recombinant enzyme
0.00061
N2-[(benzyloxy)carbonyl]-N-[(2S)-1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl]-L-leucinamide
Foot-and-mouth disease virus
-
pH 8.0, 37°C, recombinant enzyme
0.00064
N2-[(benzyloxy)carbonyl]-N-[(2S)-1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl]-L-leucinamide
Norwalk virus
pH 8.0, 37°C, recombinant enzyme
0.00099
N2-[(benzyloxy)carbonyl]-N-[(2S)-1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl]-L-leucinamide
Transmissible gastroenteritis virus
pH 6.0, 37°C, recombinant enzyme
0.00118
N2-[(benzyloxy)carbonyl]-N-[(2S)-1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl]-L-leucinamide
Human calicivirus Hu/NLV/GII/MD145-12/1987/US
-
pH 8.0, 37°C, recombinant enzyme
0.00348
N2-[(benzyloxy)carbonyl]-N-[(2S)-1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl]-L-leucinamide
Severe acute respiratory syndrome-related coronavirus
-
pH 6.0, 37°C, recombinant enzyme
0.05
N2-[(benzyloxy)carbonyl]-N-[(2S)-1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl]-L-leucinamide
Hepatovirus A
-
above, pH 8.0, 37°C, recombinant enzyme
0.00055
N2-[(benzyloxy)carbonyl]-N-[(2S)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)-4-(propan-2-ylamino)butan-2-yl]-L-leucinamide
Foot-and-mouth disease virus
-
pH 8.0, 37°C, recombinant enzyme
0.00155
N2-[(benzyloxy)carbonyl]-N-[(2S)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)-4-(propan-2-ylamino)butan-2-yl]-L-leucinamide
Transmissible gastroenteritis virus
pH 6.0, 37°C, recombinant enzyme
0.00287
N2-[(benzyloxy)carbonyl]-N-[(2S)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)-4-(propan-2-ylamino)butan-2-yl]-L-leucinamide
Norwalk virus
pH 8.0, 37°C, recombinant enzyme
0.00402
N2-[(benzyloxy)carbonyl]-N-[(2S)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)-4-(propan-2-ylamino)butan-2-yl]-L-leucinamide
Human calicivirus Hu/NLV/GII/MD145-12/1987/US
-
pH 8.0, 37°C, recombinant enzyme
0.00466
N2-[(benzyloxy)carbonyl]-N-[(2S)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)-4-(propan-2-ylamino)butan-2-yl]-L-leucinamide
Severe acute respiratory syndrome-related coronavirus
-
pH 6.0, 37°C, recombinant enzyme
0.0426
N2-[(benzyloxy)carbonyl]-N-[(2S)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)-4-(propan-2-ylamino)butan-2-yl]-L-leucinamide
Hepatovirus A
-
pH 8.0, 37°C, recombinant enzyme
0.0007
rupintrivir
Human calicivirus Hu/NLV/GII/MD145-12/1987/US
-
pH 8.0, 37°C, recombinant enzyme
0.05
rupintrivir
Transmissible gastroenteritis virus
above, pH 6.0, 37°C, recombinant enzyme
0.05
rupintrivir
Severe acute respiratory syndrome-related coronavirus
-
above, pH 6.0, 37°C, recombinant enzyme
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pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
37
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TEMPERATURE RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
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GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
drug target
physiological function
additional information
drug target
the enzyme is an attractive target for the discovery of norovirus therapeutics and prophylactics. In order to gain insight and understanding into the interaction of macrocyclic inhibitors with the enzyme, as well as probe the effect of ring size on pharmacological activity and cellular permeability, additional macrocyclic inhibitors are synthesized and high resolution cocrystal structures determined. The macrocyclic scaffold may hamper optimal binding to the active site by impeding concerted cross-talk between the S2 and S4 subsites
drug target
-
the enzyme is an attractive target for the discovery of norovirus therapeutics and prophylactics. In order to gain insight and understanding into the interaction of macrocyclic inhibitors with the enzyme, as well as probe the effect of ring size on pharmacological activity and cellular permeability, additional macrocyclic inhibitors are synthesized and high resolution cocrystal structures determined. The macrocyclic scaffold may hamper optimal binding to the active site by impeding concerted cross-talk between the S2 and S4 subsites
-
physiological function
-
the enzyme is required for viral polyprotein processing
physiological function
-
the Calicivirus proteases cleaves the viral precursor polyprotein encoded by open reading frame1 into multiple intermediate and mature proteins. The Calicivirus protease is a Cys protease with catalytic Cys104, and the His27-Asp44-Cys104 catalytic triad formation is important for protease activity. The substrate recognition mechanism may be different between Caliciviridae, i.e. the Rabbit hemorrhagic disease virus and Sapporo virus proteases and the Norwalk virus and Feline calicivirus proteases. RHDV protease critically needs the acidic residue during catalysis
physiological function
-
the Calicivirus proteases cleaves the viral precursor polyprotein encoded by open reading frame1 into multiple intermediate and mature proteins. The Calicivirus protease is a Cys protease with catalytic Cys116, and the His31-Glu52-Cys116 catalytic triad formation is important for protease activity. The substrate recognition mechanism may be different between Caliciviridae, i.e. the Rabbit hemorrhagic disease virus and Sapporo virus proteases and the Norwalk virus and Feline calicivirus proteases. SaV protease critically needs the acidic residue during catalysis
physiological function
-
the Calicivirus proteases cleaves the viral precursor polyprotein encoded by open reading frame1 into multiple intermediate and mature proteins. The Calicivirus protease is a Cys protease with catalytic Cys122, and the His39-Glu60-Cys122 catalytic triad formation is important for protease activity. The substrate recognition mechanism may be different between Caliciviridae, i.e. the Rabbit hemorrhagic disease virus and Sapporo virus proteases and the Norwalk virus and Feline calicivirus proteases. Proteolytic cleavage occurs at several cleavage sites in the ORF1 polyprotein without a functional acid residue in the FCV protease
physiological function
-
the Calicivirus proteases cleaves the viral precursor polyprotein encoded by open reading frame1 into multiple intermediate and mature proteins. The Calicivirus protease is a Cys protease with catalytic Cys139, and the His30-Glu54-Cys139 catalytic triad formation is important for protease activity. The substrate recognition mechanism may be different between Caliciviridae, i.e. the Rabbit hemorrhagic disease virus and Sapporo virus proteases and the Norwalk virus and Feline calicivirus proteases. Proteolytic cleavage occurs at several cleavage sites in the ORF1 polyprotein without a functional acid residue in the NoV protease
physiological function
noroviruses have a single-stranded, positive sense 7 to 8 kb RNA genome which encodes a polyprotein precursor that is processed by a virus-encoded 3C-like cysteine protease (NV 3CLpro) to generate at least six mature nonstructural proteins. Processing of the polyprotein is essential for virus replication
physiological function
the feline calicivirus strain 2280 proteinase-polymerase protein can suppress luciferase reporter gene expression driven by endogenous and exogenous promoters. The N-terminal 263 amino acids of proteinase-polymerase (PPN-263) determine its shut-off activity upon the expression of truncated proteins. The same domain of the feline calicivirus strain F9 proteionase-polymeraseprotein fails to inhibit gene expression. Residues Val27, Ala96 and Ala98 are key sites for the inhibition of host gene expression by strain 2280 PPN-263, and PPN-263 exhibits the ability to shut off host gene expression as long as it contains any two of the three amino acids
physiological function
feline calicivirus 2280
-
the feline calicivirus strain 2280 proteinase-polymerase protein can suppress luciferase reporter gene expression driven by endogenous and exogenous promoters. The N-terminal 263 amino acids of proteinase-polymerase (PPN-263) determine its shut-off activity upon the expression of truncated proteins. The same domain of the feline calicivirus strain F9 proteionase-polymeraseprotein fails to inhibit gene expression. Residues Val27, Ala96 and Ala98 are key sites for the inhibition of host gene expression by strain 2280 PPN-263, and PPN-263 exhibits the ability to shut off host gene expression as long as it contains any two of the three amino acids
-
physiological function
-
the feline calicivirus strain 2280 proteinase-polymerase protein can suppress luciferase reporter gene expression driven by endogenous and exogenous promoters. The N-terminal 263 amino acids of proteinase-polymerase (PPN-263) determine its shut-off activity upon the expression of truncated proteins. The same domain of the feline calicivirus strain F9 proteionase-polymeraseprotein fails to inhibit gene expression. Residues Val27, Ala96 and Ala98 are key sites for the inhibition of host gene expression by strain 2280 PPN-263, and PPN-263 exhibits the ability to shut off host gene expression as long as it contains any two of the three amino acids
-
physiological function
-
noroviruses have a single-stranded, positive sense 7 to 8 kb RNA genome which encodes a polyprotein precursor that is processed by a virus-encoded 3C-like cysteine protease (NV 3CLpro) to generate at least six mature nonstructural proteins. Processing of the polyprotein is essential for virus replication
-
additional information
-
acidic amino acid (Glu or Asp), as well as the His and Cys in the putative catalytic triad, cannot be replaced by Ala for normal processing activity of the ORF1 polyprotein in vitro. Similarly, normal activity is not retained if the nucleophile Cys is replaced with Ser
additional information
-
acidic amino acid (Glu or Asp), as well as the His and Cys in the putative catalytic triad, cannot be replaced by Ala for normal processing activity of the ORF1 polyprotein in vitro. Similarly, normal activity is not retained if the nucleophile Cys is replaced with Ser
additional information
-
acidic amino acid (Glu or Asp), as well as the His and Cys in the putative catalytic triad, cannot be replaced by Ala for normal processing activity of the ORF1 polyprotein in vitro. Similarly, normal activity is not retained if the nucleophile Cys is replaced with Ser
additional information
-
acidic amino acid (Glu or Asp), as well as the His and Cys in the putative catalytic triad, cannot be replaced by Ala for normal processing activity of the ORF1 polyprotein in vitro. Similarly, normal activity is not retained if the nucleophile Cys is replaced with Ser
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UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). POLG_LORDV
Lordsdale virus (strain GII/Human/United Kingdom/Lordsdale/1993)
1699
0
189201
Swiss-Prot
other Location (Reliability: 3)
POLG_NVN68
Norwalk virus (strain GI/Human/United States/Norwalk/1968)
1789
0
198694
Swiss-Prot
other Location (Reliability: 3)
POLG_BECN1
Bovine enteric calicivirus Newbury agent-1 (isolate Bovine/UK/Newbury1/1976)
2210
0
239021
Swiss-Prot
other Location (Reliability: 4)
POLG_BECNB
Bovine enteric calicivirus NB (isolate Bovine/United States/N ebraska/1980)
2210
0
238639
Swiss-Prot
other Location (Reliability: 3)
POLG_CACV4
1929
0
214806
Swiss-Prot
other Location (Reliability: 5)
POLG_RHDV3
2344
0
256908
Swiss-Prot
other Location (Reliability: 4)
POLG_RHDVA
Rabbit hemorrhagic disease virus (strain AST89)
2344
0
256817
Swiss-Prot
other Location (Reliability: 4)
POLG_RHDVB
Rabbit hemorrhagic disease virus (strain BS89)
2344
0
256898
Swiss-Prot
other Location (Reliability: 4)
POLG_RHDVF
Rabbit hemorrhagic disease virus (strain Rabbit/Germany/FRG/1989)
2344
0
257068
Swiss-Prot
other Location (Reliability: 3)
POLG_EBHSG
2334
2
255925
Swiss-Prot
Mitochondrion (Reliability: 4)
POLG_RHDVS
Rabbit hemorrhagic disease virus (strain SD)
2344
0
257122
Swiss-Prot
other Location (Reliability: 4)
POLG_SMSV1
1879
0
209295
Swiss-Prot
other Location (Reliability: 3)
POLG_SMSV4
1214
0
135088
Swiss-Prot
other Location (Reliability: 3)
POLG_SOUV3
Southampton virus (strain GI/Human/United Kingdom/Southampton/1991)
1788
0
198582
Swiss-Prot
other Location (Reliability: 4)
POLG_SVM10
Sapporo virus (isolate GII/Human/Thailand/Mc10/2000)
2278
0
250097
Swiss-Prot
other Location (Reliability: 2)
POLG_SVM93
Sapporo virus (strain Human/United Kingdom/Manchester/1993)
2208
0
242737
Swiss-Prot
other Location (Reliability: 2)
POLG_SVSAP
Sapporo virus (isolate GI/Human/Germany/pJG-Sap01)
2280
0
251007
Swiss-Prot
other Location (Reliability: 3)
POLG_VESVA
Vesicular exanthema of swine virus serotype A48 (isolate Swine/United States/A48/1948)
1881
2
208813
Swiss-Prot
other Location (Reliability: 4)
POLG_FCVC6
1762
0
195339
Swiss-Prot
Mitochondrion (Reliability: 3)
POLG_FCVF4
1763
0
194988
Swiss-Prot
Mitochondrion (Reliability: 3)
POLG_FCVF9
1763
0
195029
Swiss-Prot
Mitochondrion (Reliability: 3)
POLG_FCVUR
Feline calicivirus (strain Cat/United States/Urbana/1960)
1763
0
194911
Swiss-Prot
Mitochondrion (Reliability: 4)
POLG_PESV
Porcine enteric sapovirus (isolate Swine/United States/Cowden/1980)
2254
0
247170
Swiss-Prot
other Location (Reliability: 4)
R1A_CVPPU
4017
18
447352
Swiss-Prot
other Location (Reliability: 4)
Q80J95_9CALI
1687
0
187473
TrEMBL
other Location (Reliability: 1)
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PDB
SCOP
CATH
UNIPROT
ORGANISM
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MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
molecular model of the protease bound with octapeptide FRLEADDG containing a cleavage site of the capsid precursor protein
-
sitting drop vapor diffusion method, using 18% (w/v) PEG 6000, 10% (v/v) DMSO, 14% methyl-2,4-pentanediol, and 0.12 M Tris-HCl, pH 8.5
-
by hanging drop vapor diffusion or sitting drop vapor diffusion at room temperature, to 1.5 and 2.2 A resolution
purified recombinant enzyme free and bound to inhibitor (2S)-2-([N-[(benzyloxy)carbonyl]-L-leucyl]amino)-1-hydroxy-3-(2-oxopyrrolidin-3-yl)propane-1-sulfonic acid, X-ray diffraction structure determination and analysis at 1.50 and 1.65 A resolution, respectively, molecular replacement
sitting drop vapor diffusion plates at 20°C, 2.25 A resolution structure of Norovirus 3CL protease in complex with a triazole-based macrocyclic inhibitor
purified recombinant enzyme bound to inhibitor GC376, X-ray diffraction structure determination and analysis at 2.25 A resolution, molecular replacement
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PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
E54L
-
the E54L mutant protease is a substrate-specificity mutant and requires large hydrophobic amino acid residues at both P4 and P2 positions of the substrate, it cleaves the sequence 133LSFE/AP between the 3B and 3C regions of norovirus polyprotein, but does not cleaves the sequence 198ATSE/GK between the 3A and 3B
C122S
-
site-directed mutagenesis, the mutant is affected in its catalytic activity of proteolytic processing
C139S
-
site-directed mutagenesis, the mutant is affected in its catalytic activity of proteolytic processing
C104S
-
site-directed mutagenesis, the mutant is affected in its catalytic activity of proteolytic processing
C116S
-
site-directed mutagenesis, the mutant is affected in its catalytic activity of proteolytic processing
additional information
additional information
-
acidic amino acid (Glu or Asp), as well as the His and Cys in the putative catalytic triad, cannot be replaced by Ala for normal processing activity of the ORF1 polyprotein in vitro. Similarly, normal activity is not retained if the nucleophile Cys is replaced with Ser
additional information
-
acidic amino acid (Glu or Asp), as well as the His and Cys in the putative catalytic triad, cannot be replaced by Ala for normal processing activity of the ORF1 polyprotein in vitro. Similarly, normal activity is not retained if the nucleophile Cys is replaced with Ser
additional information
-
acidic amino acid (Glu or Asp), as well as the His and Cys in the putative catalytic triad, cannot be replaced by Ala for normal processing activity of the ORF1 polyprotein in vitro. Similarly, normal activity is not retained if the nucleophile Cys is replaced with Ser
additional information
-
acidic amino acid (Glu or Asp), as well as the His and Cys in the putative catalytic triad, cannot be replaced by Ala for normal processing activity of the ORF1 polyprotein in vitro. Similarly, normal activity is not retained if the nucleophile Cys is replaced with Ser
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PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
Ni-NTA column chromatography and HiTrap 26/10 QFF column chroamtography
-
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CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
cloned into pET41 Ek/LIC and pET46 Ek/LIC and expressed in Escherichia coli BL21 (DE3)
expression in Escherichia coli BL21 (DE3)
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
drug development
medicine
drug development
-
the conserved key site of the enzyme may serve as attractive target for the design of broad-spectrum antivirals for multiple viruses in the supercluster
drug development
the conserved key site of the enzyme may serve as attractive target for the design of broad-spectrum antivirals for multiple viruses in the supercluster
drug development
-
the conserved key site of the enzyme may serve as attractive target for the design of broad-spectrum antivirals for multiple viruses in the supercluster
drug development
-
the conserved key site of the enzyme may serve as attractive target for the design of broad-spectrum antivirals for multiple viruses in the supercluster
drug development
the conserved key site of the enzyme may serve as attractive target for the design of broad-spectrum antivirals for multiple viruses in the supercluster
drug development
-
the conserved key site of the enzyme may serve as attractive target for the design of broad-spectrum antivirals for multiple viruses in the supercluster
drug development
-
the conserved key site of the enzyme may serve as attractive target for the design of broad-spectrum antivirals for multiple viruses in the supercluster
-
medicine
-
calicivirus 3CLpro mediates the cleavage of poly(A)-binding protein as part of its strategy to inhibit cellular translation
medicine
-
establishment of a mammalian cell-based system for analysis of human norovirus replication and, thus makes it feasible to investigate antiviral agents in mammalian cells
medicine
-
nonbacterial acute gastroenteritis and other diseases associated with viruses expressing 3Cpro, knowledge of the structure and previous mutagenesis study allows to correlate proteolysis and structure
medicine
-
norovirus precursor comprised of both the proteinase and polymerase (released from 3C-like proteinase) is a bifunctional enzyme during virus replication, which might be useful in the development of antiviral drugs of the noroviruses associated with acute gastroenteritis
medicine
Norwalk virus is the major cause of acute, epidemic, viral gastroenteritis
medicine
-
poliovirus 3Cpro mediates the cleavage of poly(A)-binding protein as part of its strategy to inhibit cellular translation
medicine
-
calicivirus 3CLpro mediates the cleavage of poly(A)-binding protein as part of its strategy to inhibit cellular translation
-
medicine
-
norovirus precursor comprised of both the proteinase and polymerase (released from 3C-like proteinase) is a bifunctional enzyme during virus replication, which might be useful in the development of antiviral drugs of the noroviruses associated with acute gastroenteritis
-
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REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Lambden, P.R.; Caul, E.O.; Ashley, C.R.; Clarke, I.N.
Sequence and genome organization of a human small round-structured (Norwalk-like) virus
Science
259
516-519
1993
Southampton virus (Q04544)
brenda
Lambden, P.R.; Liu, B.; Clarke, I.N.
A conserved sequence motif at the 5' terminus of the Southampton virus genome is characteristic of the Caliciviridae
Virus Genes
10
149-152
1995
Southampton virus (Q04544)
brenda
Liu, B.; Clarke, I.N.; Lambden, P.R.
Polyprotein processing in Southampton virus: identification of 3C-like protease cleavage sites by in vitro mutagenesis
J. Virol.
70
2605-2610
1996
Southampton virus
brenda
Liu, B.L.; Viljoen, G.J.; Clarke, I.N.; Lambden, P.R.
Identification of further proteolytic cleavage sites in the Southampton calicivirus polyprotein by expression of the viral protease in Escherichia coli
J. Gen. Virol.
80
291-296
1999
Southampton virus
brenda
Kuyumcu-Martinez, M.; Belliot, G.; Sosnovtsev, S.V.; Chang, K.O.; Green, K.Y.; Lloyd, R.E.
Calicivirus 3C-like proteinase inhibits cellular translation by cleavage of poly(A)-binding protein
J. Virol.
78
8172-8182
2004
Enterovirus C, feline calicivirus (Q66914), feline calicivirus, norovirus, norovirus MD145-12
brenda
Nakamura, K.; Someya, Y.; Kumasaka, T.; Ueno, G.; Yamamoto, M.; Sato, T.; Takeda, N.; Miyamura, T.; Tanaka, N.
A norovirus protease structure provides insights into active and substrate binding site integrity
J. Virol.
79
13685-13693
2005
Chiba virus
brenda
Belliot, G.; Sosnovtsev, S.V.; Chang, K.O.; Babu, V.; Uche, U.; Arnold, J.J.; Cameron, C.E.; Green, K.Y.
Norovirus proteinase-polymerase and polymerase are both active forms of RNA-dependent RNA polymerase
J. Virol.
79
2393-2403
2005
norovirus, norovirus MD145
brenda
Zeitler, C.E.; Estes, M.K.; Venkataram Prasad, B.V.
X-ray crystallographic structure of the Norwalk virus protease at 1.5-A resolution
J. Virol.
80
5050-5058
2006
Norwalk virus (Q83883), Norwalk virus
brenda
Asanaka, M.; Atmar, R.L.; Ruvolo, V.; Crawford, S.E.; Neill, F.H.; Estes, M.K.
Replication and packaging of Norwalk virus RNA in cultured mammalian cells
Proc. Natl. Acad. Sci. USA
19
10327-32
2006
Norwalk virus
-
brenda
Someya, Y.; Takeda, N.; Miyamura, T.
Characterization of the norovirus 3C-like protease
Virus Res.
110
91-97
2005
Chiba virus
brenda
Sosnovtsev, S.V.; Belliot, G.; Chang, K.O.; Prikhodko, V.G.; Thackray, L.B.; Wobus, C.E.; Karst, S.M.; Virgin, H.W.; Green, K.Y.
Cleavage map and proteolytic processing of the murine norovirus nonstructural polyprotein in infected cells
J. Virol.
80
7816-7831
2006
Murine norovirus
brenda
Oka, T.; Yamamoto, M.; Yokoyama, M.; Ogawa, S.; Hansman, G.S.; Katayama, K.; Miyashita, K.; Takagi, H.; Tohya, Y.; Sato, H.; Takeda, N.
Highly conserved configuration of catalytic amino acid residues among calicivirus-encoded proteases
J. Virol.
81
6798-6806
2007
feline calicivirus, Sapovirus
brenda
Lee, C.C.; Kuo, C.J.; Ko, T.P.; Hsu, M.F.; Tsui, Y.C.; Chang, S.C.; Yang, S.; Chen, S.J.; Chen, H.C.; Hsu, M.C.; Shih, S.R.; Liang, P.H.; Wang, A.H.
Structural basis of inhibition specificities of 3C and 3C-like proteases by zinc-coordinating and peptidomimetic Compounds
J. Biol. Chem.
284
7646-7655
2009
Human coronavirus 229E
brenda
Someya, Y.; Takeda, N.
Insights into the enzyme-substrate interaction in the norovirus 3C-like protease
J. Biochem.
146
509-521
2009
Chiba virus
brenda
Oka, T.; Murakami, K.; Wakita, T.; Katayama, K.
Comparative site-directed mutagenesis in the catalytic amino acid triad in Calicivirus proteases
Microbiol. Immunol.
55
108-114
2011
feline calicivirus, Norwalk virus, Rabbit hemorrhagic disease virus, Sapporo virus
brenda
Kim, Y.; Lovell, S.; Tiew, K.C.; Mandadapu, S.R.; Alliston, K.R.; Battaile, K.P.; Groutas, W.C.; Chang, K.O.
Broad-spectrum antivirals against 3C or 3C-like proteases of picornaviruses, noroviruses, and coronaviruses
J. Virol.
86
11754-11762
2012
Foot-and-mouth disease virus, Hepatovirus A, Severe acute respiratory syndrome-related coronavirus, Human calicivirus Hu/NLV/GII/MD145-12/1987/US, Transmissible gastroenteritis virus (P0C6V2), Transmissible gastroenteritis virus, Norwalk virus (Q83883), Norwalk virus, Transmissible gastroenteritis virus Purdue (P0C6V2)
brenda
Yokoyama, M.; Oka, T.; Takagi, H.; Kojima, H.; Okabe, T.; Nagano, T.; Tohya, Y.; Sato, H.
A proposal for a structural model of the feline calicivirus protease bound to the substrate peptide under physiological conditions
Front. Microbiol.
8
1383
2017
feline calicivirus, feline calicivirus F4
brenda
Kim, Y.; Shivanna, V.; Narayanan, S.; Prior, A.M.; Weerasekara, S.; Hua, D.H.; Kankanamalage, A.C.; Groutas, W.C.; Chang, K.O.
Broad-spectrum inhibitors against 3C-like proteases of feline coronaviruses and feline caliciviruses
J. Virol.
89
4942-4950
2015
feline calicivirus, feline coronavirus, feline calicivirus Urbana, feline coronavirus FIPV WSU-79/1146
brenda
Galasiti Kankanamalage, A.C.; Weerawarna, P.M.; Rathnayake, A.D.; Kim, Y.; Mehzabeen, N.; Battaile, K.P.; Lovell, S.; Chang, K.O.; Groutas, W.C.
Putative structural rearrangements associated with the interaction of macrocyclic inhibitors with norovirus 3CL protease
Proteins
87
579-587
2019
Norwalk virus (Q83883), Norwalk virus GI (Q83883)
brenda
Wu, H.; Zu, S.; Sun, X.; Liu, Y.; Tian, J.; Qu, L.
N-Terminal domain of feline calicivirus (FCV) proteinase-polymerase contributes to the inhibition of host cell transcription
Viruses
8
E199
2016
feline calicivirus, feline calicivirus (P27409), feline calicivirus 2280, feline calicivirus F9 (P27409)
brenda
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