3.4.22.69: SARS coronavirus main proteinase
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3.4.22.69
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covid-19
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pandemic
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repurposing
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outbreak
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spike
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sarma
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polyproteins
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drug development
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3-chymotrypsin-like
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boceprevir
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medicine
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favipiravir
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phytocompounds
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saquinavir
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analysis
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schrodinger
- 3.4.22.69
- covid-19
- pandemic
-
repurposing
-
outbreak
-
ramaswamy
- spike
-
sarma
- polyproteins
- coronaviruses
-
drug-likeness
-
autodock
-
protein-ligand
-
fda-approved
- lopinavir
-
rna-dependent
- remdesivir
-
admet
-
papain-like
-
lipinsky
- hydroxychloroquine
- ace2
-
anti-sars-cov-2
-
wuhan
- plpro
- nelfinavir
-
peptidomimetic
- ritonavir
-
anti-sars
-
anti-covid-19
-
mm-gbsa
-
replicase
- telaprevir
-
covid
-
drugbank
- betacoronavirus
-
syndrome-coronavirus
- coronaviral
-
warhead
- coronaviridae
- sars-cov2
- darunavir
- disease-19
-
swissadme
- drug development
-
3-chymotrypsin-like
- boceprevir
- medicine
-
pubchem
- favipiravir
-
phytocompounds
- saquinavir
- analysis
-
schrodinger
Reaction
Synonyms
2019-nCoV 3C-like protease, 3C-like cysteine protease, 3C-like peptidase, 3C-like protease, 3CL protease, 3CL-pro, 3cLpro, C30.004, chymotrypsin-like protease, coronavirus 3C-like protease, coronavirus M(pro), coronavirus main protease, main protease, MERS-CoV 3C-like protease, Mpro, nsp5, porcine transmissible gastroenteritis virus Mpro, protease Mpro, SARS 3C-like protease, SARS 3C-like proteinase, SARS 3CL protease, SARS 3CLpro, SARS coronavirus 3C-like protease, SARS coronavirus 3C-like proteinase, SARS coronavirus 3CL protease, SARS coronavirus main peptidase, SARS coronavirus main protease, SARS coronavirus main proteinase, SARS coronavirus Mpro, SARS CoV main proteinase, SARS CoVMpro, SARS main protease, SARS Mpro, SARS-3CL protease, SARS-3CLpro, SARS-coronavirus 3CL protease, SARS-coronavirus main protease, SARS-CoV 3C-like peptidase, SARS-CoV 3C-like protease, SARS-CoV 3CL peptidase, SARS-CoV 3CL protease, SARS-CoV 3CLpro, SARS-CoV 3CLpro enzyme, SARS-CoV 3CLpro protease, SARS-CoV main protease, SARS-CoV Mpro, SARS-CoV nsp5-pp1a/pp1ab 3CL protease, SARS-CoV-2 3C-like protease, SARS-CoV-2 main protease, SARSCoV main protease, SARSCoV Mpro, severe acute respiratory syndrome coronavirus 3C-like protease, severe acute respiratory syndrome coronavirus 3CLpro, severe acute respiratory syndrome coronavirus main protease, severe acute respiratory syndrome coronavirus main proteinase, severe acute respiratory syndrome coronavirus Mpro, TGEV Mpro
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Engineering on EC 3.4.22.69 - SARS coronavirus main proteinase
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PROTEIN VARIANTS 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
A252S
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A252S mutation in 3CLpro confers an 1.15fold increase in the IC50 value for the inhibitor GC376 and a 1.24fold increase in the IC50 value for the inhibitor NPI52
K260N
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K260N mutation in 3CLpro confers an 1.05fold increase in the IC50 value for the inhibitor GC376
N25S
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N25S mutation in 3CLpro confers an 1.38fold increase in the IC50 value for the inhibitor GC376 and a 1.54fold increase in the IC50 value for the inhibitor NPI52
N25S/A252S/K260N
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N25S/A252S/K260N mutation in 3CLpro confers an 1.68fold increase in the IC50 value for the inhibitor GC376 and a 1.06fold increase in the IC50 value for the inhibitor NPI52
N25S/K260N
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N25S/K260N mutation in 3CLpro confers an 1.53fold increase in the IC50 value for the inhibitor GC376 and a 1.33fold increase in the IC50 value for the inhibitor NPI52
F139A
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loss in protease activity. Significant disruption of the intermolecular hydrogen bonding network and intermolecular dynamic correlations for the active sites, thus affecting the intermolecular hydrogen bond network and the substrate binding affinity
G142A
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loss in protease activity. Significant disruption of the intermolecular hydrogen bonding network and intermolecular dynamic correlations for the active sites, thus affecting the intermolecular hydrogen bond network and the substrate binding affinity
H162A
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loss in protease activity. Significant disruption of the intermolecular hydrogen bonding network and intermolecular dynamic correlations for the active sites, thus affecting the intermolecular hydrogen bond network and the substrate binding affinity
W31A
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loss in protease activity. Mutation might cause subtle but significant rearrangements in the structure resulting in altered interactions with the bound substrate, as well as impacting the dynamic assemblies of the complexes
F140A
mutant F140A is a dimer with the most collapsed active pocket discovered so far, well-reflecting the stabilizing role of this residue, the mutant enzyme is completely inactive
S139A
mutant S139A is a monomer that still retains a small fraction of dimer in solution, which may account for its remaining activity
C145A
P108S
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patients infected with a SARS-Cov-2 sub-lineage (B.1.1.284) carrying the Pro108Ser mutation in 3CLpro tend to have a comparatively milder clinical course than patients infected with the same sub-lineage of virus not carrying the mutation. The Kcat/Km value of the 3CLpro enzyme containing Ser108 is 58% lower than that of Pro108 3CLpro. The reduced activity is associated with structural perturbation surrounding the substrate-binding region of the enzyme
C145A
C300A
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mutant enzyme shows more than 30% of wild-type activity
E14A
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the ratio of dimer to monomer in solution is 0.36, compared to 1 for the wild-type enzyme
E166A
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involved in connecting the substrate binding site with the dimer interface, dimerization influenced by substrate binding
E288A
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mutant enzyme retains less than 10% of the wild-type activity
F140A
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the ratio of dimer to monomer in solution is 0.63, compared to 1 for the wild-type enzyme
F291A
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activity is higher than that of wild-type enzyme
F3A
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the ratio of dimer to monomer in solution is 0.93, compared to 1 for the wild-type enzyme
G11A/L141T/R298A/Q299A
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mutant is enzymatically active as a monomer, about 2% of wild-type activity
G283A
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no significant activity differences from the wild-type protease
I286A
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activity is higher than that of wild-type enzyme
L282A
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mutant enzyme shows more than 30% of wild-type activity
N214A
N289A
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mutant enzyme retains less than 10% of the wild-type activity
N28A
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the mutation almost completely inactivates the enzyme and results in decreased dimerization
Q189A
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kcat for the substrate [4-(4-dimethylaminophenylazo)benzoic acid]-KNSTLQSGLRKE-[5-[2'-(aminoethyl)amino]-naphthalenesulfonic acid] is 1.14 fold lower than wild-type value, Km-value for the substrate [4-(4-dimethylaminophenylazo)benzoic acid]-KNSTLQSGLRKE-[5-[2'-(aminoethyl)amino]-naphthalenesulfonic acid] is 1.3fold lower than the wild-type value
Q1N
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site-directed mutagenesis, the mutation results in loss of cleavage at this site
Q290A
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mutant enzyme retains less than 10% of the wild-type activity
Q299A
Q306N
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site-directed mutagenesis, the mutation results in loss of cleavage at this site
R188I
R298A
R298A/Q299A
R298K
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mutation has no significant effect on activity
R298L
R4A
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the ratio of dimer to monomer in solution is 0.45, compared to 1 for the wild-type enzyme
S10A
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the ratio of dimer to monomer in solution is 0.66, compared to 1 for the wild-type enzyme
S123A
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mutation does not destroy the enzyme activity, the dimeric structure remains intact
S123C
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mutation does not destroy the enzyme activity, the dimeric structure remains intact
S139A
S1A
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the ratio of dimer to monomer in solution is 1.08, compared to 1 for the wild-type enzyme
S284A
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activity is higher than that of wild-type enzyme
S284A/T285A/I286A
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activity is 3.7fold higher than wild-type activity
S301A
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no significant activity differences from the wild-type protease
T25G
T25S
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almost complete loss of activity
T280A
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no significant activity differences from the wild-type protease
T285A
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activity is higher than that of wild-type enzyme
N28A
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the mutation almost completely inactivates the enzyme and results in decreased dimerization
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additional information
C145A
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no irreversible inactivation by benzotriazole esters
C145A
catalytic-site mutation, in which the enzyme binds the C-terminal prosequence of another enzyme molecule
N214A
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mutant enzyme shows more than 30% of wild-type activity
N214A
the mutant shows reduced activity but still remains dimeric. Mutation inactivates the catalytic machinery by decoupling the network
Q299A
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mutant enzyme retains less than 10% of the wild-type activity
Q299A
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the quaternary structures of exists in a mixture of monomeric and dimeric forms
R188I
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replacing Arg with Ile at position 188 renders the protease resistant to proteolysis. The catalytic ability of 3CL-R188I protease was found to be extreme as compared to that of a mature 3CL protease containing a C-terminal His tag. The kcat values is 0.0203 per sec for mature 3CL protease and 4753 per sec for the 3CL-R188I
R188I
the enzymatic efficiency of the R188I mutant is increased by a factor of more than 1 million
R188I
auto-proteolysis resistant mutant
R188I
mature SARS 3CLpro is sensitive to degradation at the 188Arg/189Gln site, and the Arg188Ile mutant is resistant to this degradation
R298A
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mutant enzyme retains less than 10% of the wild-type activity
R298A
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the quaternary structures of exists in a mixture of monomeric and dimeric forms
R298A
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induce dimer dissociation (influenced by substrate binding), about 10fold decrease in activity
R298A
site-directed mutagenesis, the enzyme mutant shows a reversible substrate-induced dimerization that is essential for catalysis. In substrate-bound mutant enzyme crystals, a dimer with a mutual orientation of the monomers that differs from that of the wild-type protease is present in the asymmetric unit. The presence of a complete substrate-binding pocket and oxyanion hole in both protomers suggests that they are both catalytically active, while the two domain IIIs show minor reorganization. Reorganization of the dimer in the R298A mutant, verview
R298A
inactive monomeric mutant enzyme
R298A/Q299A
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mutant is present almost exclusively in the monomeric form
R298A/Q299A
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monomer, no activity detected
R298L
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mutation destroys 85% of the enzyme activity
R298L
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induce dimer dissociation (influenced by substrate binding), about 10fold decrease in activity
S139A
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mutation can destroy neither the enzyme activity nor the dimeric structure
S139A
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mutation does not destroy the enzyme activity, the dimeric structure remains intact
S139A
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the ratio of dimer to monomer in solution is 0.81, compared to 1 for the wild-type enzyme
T25G
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activity like wild-type (substrate DABCYL-Lys-Thr-Ser-Ala-Val-Leu-Gln-Ser-Gly-Phe-Arg-Lys-Met-Glu-EDANS), higher specific activity than wild-type protein for substrate Ser-Ala-Val-Leu-Gln-Met-Gly-Phe-Arg-Lys
T25G
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the mutant enzyme has an expanded S1' space that demonstrates 43.5-fold better kcat/Km compared with wild type in cleaving substrates with a larger Met at P1', mutant enzyme T25G shows a 12fold and 8fold higher activity against the substrates with Met and Leu at P1', respectively
additional information
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comparison of the amino acid sequences of feline coronavirus 3CLpro from the pre-treatment ascites sample and the postmortem tissue samples of Felis catus shows amino acid changes of N25S and K260N in the kidney and N25S, A252S and K260N in the lung and spleen
additional information
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truncation of C-terminus from 306 to 300 has no appreciable effect on the quaternary structure, and the enzyme remains catalytically active. Further deletion of Gln299 or Arg298 drastically decreases the enzyme activity to 12% of wild type, and the major form is a monomeric one. The catalytic constant and specificity constant (kcat/Km) of the proteases are significantly decreased in the DELTA(299306), DELTA(298306), and DELTA(297306) mutants. Wild type and DELTA(300306) proteases exist with dimer as the major form. The major form becomes monomeric in DELTA(299306), DELTA(298306) and DELTA(297306)
additional information
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without the N-finger, SARS-CoV Mpro can no longer retain the active dimer structure. It can form a new type of dimer which is inactive. Therefore, the N-finger of SARS-CoV Mpro is not only critical for its dimerization but also essential for the enzyme to form the enzymatically active dimer
additional information
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development of a SARS 3CL protease autoprocessing system by use of the Escherichia coli cell-free protein synthesis system, with the N- and C-terminal 10 amino acid pro-sequences accompanied by an S-tag and a His-tag, respectively
