Literature summary for 3.4.22.B50 extracted from

  • Baez-Santos, Y.M.; St John, S.E.; Mesecar, A.D.
    The SARS-coronavirus papain-like protease: structure, function and inhibition by designed antiviral compounds (2015), Antiviral Res., 115, 21-38.
    View publication on PubMedView publication on EuropePMC

Application

Application Comment Organism
drug development the enzyme is an attractive antiviral drug target because it is essential for coronaviral replication. Targeting the enzyme with antiviral drugs may have an advantage in not only inhibiting viral replication but also inhibiting the dysregulation of signaling cascades in infected cells that may lead to cell death in surrounding, uninfected cells Severe acute respiratory syndrome-related coronavirus

Crystallization (Commentary)

Crystallization (Comment) Organism
apoenzyme and enzyme in complexes with ubiquitin, and inhibitors 5-amino-2-methyl-N-[(1R)-1-(naphthalen-1-yl)ethyl]benzamide, N-(1,3-benzodioxol-5-ylmethyl)-1-[(1R)-1-(naphthalen-1-yl)ethyl]piperidine-4-carboxamide, N-(4-fluorobenzyl)-1-[(1R)-1-(naphthalen-1-yl)ethyl]piperidine-4-carboxamide, and N-(3-fluorobenzyl)-1-[(1R)-1-(naphthalen-1-yl)ethyl]piperidine-4-carboxamide, sitting drop vapor diffusion method, apoenzyme by mixing of 1.1-20 mg/ml protein in 20 mM Tris, pH 7.5, 10 mM DTT, with 100 mM sodium citrate, pH 5.2, 3 M ammonium sulfate. Enzyme-inhibitor N-(1,3-benzodioxol-5-ylmethyl)-1-[(1R)-1-(naphthalen-1-yl)ethyl]piperidine-4-carboxamide complex by mixing of 5 mg/ml protein in 20 mM Tris, pH 7.5, 10 mM DTT, with 1 mM inhibitor, 1 M (NH4)2SO4, 50 mM MES, pH 6.5, and 2.5% PEG 400. Enzyme-inhibitor 5-amino-2-methyl-N-[(1R)-1-(naphthalen-1-yl)ethyl]benzamide by mixing of 8 mg/ml protein in 20 mM Tris, pH 7.5, 10 mM DTT with 0.20 mM inhibitor, 1 M LiCl2, 0.1 M MES pH 6.0, 30% PEG 6000. Enzyme-inhibitor N-(3-fluorobenzyl)-1-[(1R)-1-(naphthalen-1-yl)ethyl]piperidine-4-carboxamide or N-(4-fluorobenzyl)-1-[(1R)-1-(naphthalen-1-yl)ethyl]piperidine-4-carboxamide complex by mixing of 6 and 12 mg/ml protein, respectively, in 25 mM Tris, pH 7.5, 100 mM NaCl, 10 mM DTT with 0.20 mM inhibitor, 100 mM sodium citrate, pH 5.5, 40% v/v PEG 600. Enzyme-ubiquitin complex by mixing of 3-12 mg/ml protein and ubiquitin in 20 mM Tris, pH 7.5, with 0.1 M CHES, pH 9.5, 18% PEG 3000, X-ray diffraction structure determination and analysis at 1.4-2.75 A resolution Severe acute respiratory syndrome-related coronavirus

Engineering

Protein Variants Comment Organism
C112S site-directed mutagenesis, active site cysteine mutant, forms a noncovalent complex with ubiquitin, crystal structure analysis Severe acute respiratory syndrome-related coronavirus

Inhibitors

Inhibitors Comment Organism Structure
1,6,6-trimethyl-1,2,6,7,8,9-hexahydrophenanthro[1,2-b]furan-10,11-dione a natural tanshinone inhibitor Severe acute respiratory syndrome-related coronavirus
2-methyl-N-[1-(naphthalen-2-yl)ethyl]benzamide racemat Severe acute respiratory syndrome-related coronavirus
2-methyl-N-[(1R)-1-(naphthalen-2-yl)ethyl]benzamide over 90% inhibition at 0.1 mM Severe acute respiratory syndrome-related coronavirus
2-methyl-N-[(1S)-1-(naphthalen-2-yl)ethyl]benzamide 14% inhibition at 0.1 mM Severe acute respiratory syndrome-related coronavirus
(4E)-1,7-bis(3,4-dihydroxyphenyl)hept-4-en-3-one a natural diarylheptanoide inhibitor Severe acute respiratory syndrome-related coronavirus
5-amino-2-methyl-N-[(1R)-1-(naphthalen-1-yl)ethyl]benzamide R-isomer, a potent, noncovalent, competitive inhibitor Severe acute respiratory syndrome-related coronavirus
6-Mercaptopurine
-
Severe acute respiratory syndrome-related coronavirus
6-thioguanine
-
Severe acute respiratory syndrome-related coronavirus
(7R)-5,7-dihydroxy-8-(4-hydroxy-3-methoxyphenyl)-2-(4-hydroxy-4-methylpentyl)-2-methyl-3,4,7,8-tetrahydro-2H,6H-pyrano[3,2-g]chromen-6-one a natural geranylated flavonoid inhibitor Severe acute respiratory syndrome-related coronavirus
Cu2+ 30% inhibition at 0.01 mM Severe acute respiratory syndrome-related coronavirus
hydroxypyridine-2-thione-Zn(II)
-
Severe acute respiratory syndrome-related coronavirus
additional information enzyme structure, function and inhibition by designed antiviral compounds, overview. No inhibition by NSC158362. Selectivity of naphthalene-based enzyme inhibitors, overview Severe acute respiratory syndrome-related coronavirus
N-(1,3-benzodioxol-5-ylmethyl)-1-[(1R)-1-(naphthalen-1-yl)ethyl]piperidine-4-carboxamide
-
Severe acute respiratory syndrome-related coronavirus
N-[(2-methoxypyridin-4-yl)methyl]-1-[(1R)-1-(naphthalen-1-yl)ethyl]piperidine-4-carboxamide
-
Severe acute respiratory syndrome-related coronavirus
N-[3-(acetylamino)benzyl]-1-[(1R)-1-(naphthalen-1-yl)ethyl]piperidine-4-carboxamide
-
Severe acute respiratory syndrome-related coronavirus
N-(3-fluorobenzyl)-1-[(1R)-1-(naphthalen-1-yl)ethyl]piperidine-4-carboxamide
-
Severe acute respiratory syndrome-related coronavirus
N-(4-fluorobenzyl)-1-[(1R)-1-(naphthalen-1-yl)ethyl]piperidine-4-carboxamide
-
Severe acute respiratory syndrome-related coronavirus
N-(4-methoxybenzyl)-1-(naphthalen-1-ylmethyl)piperidine-4-carboxamide
-
Severe acute respiratory syndrome-related coronavirus
N-ethyl-N-phenyldithiocarbamic acid-Zn(II)
-
Severe acute respiratory syndrome-related coronavirus
NSC158011
-
Severe acute respiratory syndrome-related coronavirus

Metals/Ions

Metals/Ions Comment Organism Structure
additional information no effect by Mg2+, Ca2+, Mn2+, Co2+, and Ni2+ Severe acute respiratory syndrome-related coronavirus
Zn2+ the fingers domain of the enzyme contains a zinc ion that is tetrahedrally coordinated by four cysteines Severe acute respiratory syndrome-related coronavirus

Organism

Organism UniProt Comment Textmining
Severe acute respiratory syndrome-related coronavirus
-
from the Guangdong Province of China
-

Synonyms

Synonyms Comment Organism
PLpro
-
Severe acute respiratory syndrome-related coronavirus
SARS-coronavirus papain-like protease
-
Severe acute respiratory syndrome-related coronavirus
SARS-CoV papain-like protease
-
Severe acute respiratory syndrome-related coronavirus
SARS-CoV PLpro
-
Severe acute respiratory syndrome-related coronavirus

Ki Value [mM]

Ki Value [mM] Ki Value maximum [mM] Inhibitor Comment Organism Structure
0.00049
-
5-amino-2-methyl-N-[(1R)-1-(naphthalen-1-yl)ethyl]benzamide pH and temperature not specified in the publication Severe acute respiratory syndrome-related coronavirus

IC50 Value

IC50 Value IC50 Value Maximum Comment Organism Inhibitor Structure
0.0008
-
pH and temperature not specified in the publication Severe acute respiratory syndrome-related coronavirus 1,6,6-trimethyl-1,2,6,7,8,9-hexahydrophenanthro[1,2-b]furan-10,11-dione
0.005
-
pH and temperature not specified in the publication Severe acute respiratory syndrome-related coronavirus 6-thioguanine
0.005
-
pH and temperature not specified in the publication Severe acute respiratory syndrome-related coronavirus (7R)-5,7-dihydroxy-8-(4-hydroxy-3-methoxyphenyl)-2-(4-hydroxy-4-methylpentyl)-2-methyl-3,4,7,8-tetrahydro-2H,6H-pyrano[3,2-g]chromen-6-one
0.00039
-
pH and temperature not specified in the publication Severe acute respiratory syndrome-related coronavirus N-[3-(acetylamino)benzyl]-1-[(1R)-1-(naphthalen-1-yl)ethyl]piperidine-4-carboxamide
0.00015
-
pH and temperature not specified in the publication Severe acute respiratory syndrome-related coronavirus N-(3-fluorobenzyl)-1-[(1R)-1-(naphthalen-1-yl)ethyl]piperidine-4-carboxamide
0.00032
-
pH and temperature not specified in the publication Severe acute respiratory syndrome-related coronavirus N-(1,3-benzodioxol-5-ylmethyl)-1-[(1R)-1-(naphthalen-1-yl)ethyl]piperidine-4-carboxamide
0.0037
-
pH and temperature not specified in the publication Severe acute respiratory syndrome-related coronavirus hydroxypyridine-2-thione-Zn(II)
0.0006
-
pH and temperature not specified in the publication Severe acute respiratory syndrome-related coronavirus 5-amino-2-methyl-N-[(1R)-1-(naphthalen-1-yl)ethyl]benzamide
0.0041
-
pH and temperature not specified in the publication Severe acute respiratory syndrome-related coronavirus (4E)-1,7-bis(3,4-dihydroxyphenyl)hept-4-en-3-one
0.0087
-
pH and temperature not specified in the publication Severe acute respiratory syndrome-related coronavirus 2-methyl-N-[(1R)-1-(naphthalen-2-yl)ethyl]benzamide
0.00035
-
pH and temperature not specified in the publication Severe acute respiratory syndrome-related coronavirus N-[(2-methoxypyridin-4-yl)methyl]-1-[(1R)-1-(naphthalen-1-yl)ethyl]piperidine-4-carboxamide
0.059
-
pH and temperature not specified in the publication Severe acute respiratory syndrome-related coronavirus N-(4-methoxybenzyl)-1-(naphthalen-1-ylmethyl)piperidine-4-carboxamide
0.0033
-
pH and temperature not specified in the publication Severe acute respiratory syndrome-related coronavirus N-ethyl-N-phenyldithiocarbamic acid-Zn(II)
0.00049
-
pH and temperature not specified in the publication Severe acute respiratory syndrome-related coronavirus N-(4-fluorobenzyl)-1-[(1R)-1-(naphthalen-1-yl)ethyl]piperidine-4-carboxamide
0.0201
-
racemate, pH and temperature not specified in the publication Severe acute respiratory syndrome-related coronavirus 2-methyl-N-[1-(naphthalen-2-yl)ethyl]benzamide
0.0216
-
pH and temperature not specified in the publication Severe acute respiratory syndrome-related coronavirus 6-Mercaptopurine

General Information

General Information Comment Organism
physiological function the primary function of the enzyme is to process the viral polyprotein in a coordinated manner. An additional function of the enzyme is stripping ubiquitin and ISG15 from host-cell proteins to aid the coronavirus in the evasion of the host innate immune responses, enzyme innate immune functions, overview Severe acute respiratory syndrome-related coronavirus
additional information enzyme structure and function, active site structure with catalytic triad residues, Cys112, His273 and Asp287 and the oxyanion hole-stabilizing residue Trp107, and catalytic mechanism, detailed overview. The fingers domain of PLpro, which contains a zinc ion that is tetrahedrally coordinated by four cysteines, is essential for catalysis because it maintains the structural integrity of the enzyme Severe acute respiratory syndrome-related coronavirus