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.

Search for more literature for 3.4.22.B50

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

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

Protein Variants

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
(4E)-1,7-bis(3,4-dihydroxyphenyl)hept-4-en-3-one	a natural diarylheptanoide inhibitor	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
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-[(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
2-methyl-N-[1-(naphthalen-2-yl)ethyl]benzamide	racemat	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
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-(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
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
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	-

Reaction

Reaction	Comment	Organism	Reaction ID
responsible for the cleavages located at the N-terminus of the replicase polyprotein	catalytic cycle and proposed chemical mechanism of the SARS-coronavirus papain-like protease catalyzed reaction, of the catalytic triad residues Cys112 acts as nucleophile, His273 functions as a general acid-base, and Asp287 is paired with histidine helping to align it and promote deprotonation of Cys112, structure-function relationship, overview	Severe acute respiratory syndrome-related coronavirus	a

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
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
0.00035	-	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
0.00039	-	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
0.00049	-	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
0.0006	-	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
0.0008	-	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
0.0033	-	pH and temperature not specified in the publication	Severe acute respiratory syndrome-related coronavirus	N-ethyl-N-phenyldithiocarbamic acid-Zn(II)
0.0037	-	pH and temperature not specified in the publication	Severe acute respiratory syndrome-related coronavirus	hydroxypyridine-2-thione-Zn(II)
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
0.005	-	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
0.0087	-	pH and temperature not specified in the publication	Severe acute respiratory syndrome-related coronavirus	2-methyl-N-[(1R)-1-(naphthalen-2-yl)ethyl]benzamide
0.0201	-	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
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

General Information

General Information	Comment	Organism
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
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