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Information on EC 3.4.22.66 - calicivirin and Organism(s) Norwalk virus and UniProt Accession Q83883

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EC Tree
     3 Hydrolases
         3.4 Acting on peptide bonds (peptidases)
             3.4.22 Cysteine endopeptidases
                3.4.22.66 calicivirin
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This record set is specific for:
Norwalk virus
UNIPROT: Q83883 not found.
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The taxonomic range for the selected organisms is: Norwalk virus
The enzyme appears in selected viruses and cellular organisms
Reaction Schemes
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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
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
3C-like cysteine protease
-
3C-like protease
-
NV protease
-
viral cysteine protease
-
3C-like viral protease
-
-
-
-
3Cpro
-
-
-
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C37.001
-
-
-
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calicivirus protease
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Southampton virus 3C-like protease
-
-
-
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
hydrolysis of peptide bond
-
-
-
-
CAS REGISTRY NUMBER
COMMENTARY hide
218925-73-6
-
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
Edans-DFHLQGP-Dabcyl + H2O
Edans-DFHLQ + GP-Dabcyl
show the reaction diagram
ORF1 polyprotein + H2O
six nonstructural proteins for replication
show the reaction diagram
-
-
-
?
ORF1 polyprotein + H2O
nonstructural proteins
show the reaction diagram
-
-
-
-
?
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
(2S)-2-([N-[(benzyloxy)carbonyl]-L-leucyl]amino)-1-hydroxy-3-(2-oxopyrrolidin-3-yl)propane-1-sulfonic acid
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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
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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
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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
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N2-[(benzyloxy)carbonyl]-N-[(2S)-1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl]-L-leucinamide
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N2-[(benzyloxy)carbonyl]-N-[(2S)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)-4-(propan-2-ylamino)butan-2-yl]-L-leucinamide
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phenylmethylsulfonyl fluoride
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rupintrivir
-
additional information
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
Glu 54
active role in proteolysis
-
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
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
0.0016
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
0.00064
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
0.00287
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
0.00083
rupintrivir
Norwalk virus
pH 8.0, 37°C, recombinant enzyme
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
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
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
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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
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
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
dimer
size exclusion chromatography results
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
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
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
E54A
Glu at the active centre
C139S
-
site-directed mutagenesis, the mutant is affected in its catalytic activity of proteolytic processing
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
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
by nickel affinity chromatography or size exclusion chromatography
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
cloned into pET41 Ek/LIC and pET46 Ek/LIC and expressed in Escherichia coli BL21 (DE3)
expression in HEK293 cells
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
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
Norwalk virus is the major cause of acute, epidemic, viral gastroenteritis
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
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
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
Manually annotated by BRENDA team
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
-
Manually annotated by BRENDA team
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
Rabbit hemorrhagic disease virus, Norwalk virus, feline calicivirus, Sapporo virus
Manually annotated by BRENDA team
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, Human calicivirus Hu/NLV/GII/MD145-12/1987/US, Norwalk virus (Q83883), Norwalk virus, Severe acute respiratory syndrome-related coronavirus, Transmissible gastroenteritis virus (P0C6V2), Transmissible gastroenteritis virus, Transmissible gastroenteritis virus Purdue (P0C6V2)
Manually annotated by BRENDA team
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)
Manually annotated by BRENDA team