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A Mechanistic View of Enzyme Inhibition and Peptide Hydrolysis in the Active Site of the SARS-CoV 3C-like Peptidase
- Source :
- Journal of Molecular Biology
- Publication Year :
- 2007
- Publisher :
- Elsevier Ltd., 2007.
-
Abstract
- The 3C-like main peptidase 3CL(pro) is a viral polyprotein processing enzyme essential for the viability of the Severe Acute Respiratory Syndrome coronavirus (SARS-CoV). While it is generalized that 3CL(pro) and the structurally related 3C(pro) viral peptidases cleave their substrates via a mechanism similar to that underlying the peptide hydrolysis by chymotrypsin-like serine proteinases (CLSPs), some of the hypothesized key intermediates have not been structurally characterized. Here, we present three crystal structures of SARS 3CL(pro) in complex with each of two members of a new class of peptide-based phthalhydrazide inhibitors. Both inhibitors form an unusual thiiranium ring with the nucleophilic sulfur atom of Cys145, trapping the enzyme's catalytic residues in configurations similar to the intermediate states proposed to exist during the hydrolysis of native substrates. Most significantly, our crystallographic data are consistent with a scenario in which a water molecule, possibly via indirect coordination from the carbonyl oxygen of Thr26, has initiated nucleophilic attack on the enzyme-bound inhibitor. Our data suggest that this structure resembles that of the proposed tetrahedral intermediate during the deacylation step of normal peptidyl cleavage.
- Subjects :
- Models, Molecular
TI, tetrahedral intermediate
Peptide
Plasma protein binding
Crystallography, X-Ray
01 natural sciences
episulfide
Protein structure
Structural Biology
Tetrahedral carbonyl addition compound
SARS, Severe Acute Respiratory Syndrome
Coronavirus 3C Proteases
inhibitor design
chemistry.chemical_classification
0303 health sciences
biology
Hydrolysis
FMDV, Foot-and-Mouth Disease Virus
CMK, chloromethylketone
Cysteine Endopeptidases
Severe acute respiratory syndrome-related coronavirus
mph, methylphthalhydrazide
Tb, (O-benzyloxy) threonine
Protein Binding
TGEV, transmissible gastroenteritis coronavirus
BCM7, β-casomorphin 7
Stereochemistry
010402 general chemistry
Cleavage (embryo)
MHV, Mouse Hepatitis Virus
Article
Catalysis
03 medical and health sciences
Viral Proteins
FMK, fluoromethylketone
HAV, Hepatitis A virus
Protease Inhibitors
Cysteine
Binding site
Molecular Biology
030304 developmental biology
Ac, acetyl
SARS
Binding Sites
3C-like proteinase
tetrahedral intermediate
Qc, cycloglutamine
Active site
Water
CLSP, chymotrypsin-like serine peptidase
Hydrogen Bonding
TFLA, trifluoroacetal-leucyl-alanyl-p-trifluoromethylphenylanilide
0104 chemical sciences
Protein Structure, Tertiary
Enzyme
chemistry
biology.protein
Subjects
Details
- Language :
- English
- ISSN :
- 10898638 and 00222836
- Volume :
- 371
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- Journal of Molecular Biology
- Accession number :
- edsair.doi.dedup.....729e9c521e7c1cce47345e27878a9c4e