Citation

Verschueren KHG, Pumpor K, Anemüller S, Chen S, Mesters JR, Hilgenfeld R. Chemistry and Biology 2008; 15(6): 597-606.

Copyright

(Copyright © 2008)

DOI

10.1016/j.chembiol.2008.04.011

PMID

18559270

PMCID

PMC7110992

Abstract

The main proteinase (M(pro)) of the severe acute respiratory syndrome (SARS) coronavirus is a principal target for the design of anticoronaviral compounds. Benzotriazole esters have been reported as potent nonpeptidic inhibitors of the enzyme, but their exact mechanism of action remains unclear. Here we present crystal structures of SARS-CoV M(pro), the active-site cysteine of which has been acylated by benzotriazole esters that act as suicide inhibitors. In one of the structures, the thioester product has been hydrolyzed and benzoic acid is observed to bind to the hydrophobic S2 pocket. This structure also features the enzyme with a shortened N-terminal segment ("amputated N finger"). The results further the understanding of the important role of the N finger for catalysis as well as the design of benzotriazole inhibitors with improved specificity.

Language: en

Keywords

Catalysis; Coronavirus 3C Proteases; Crystallization; Crystallography, X-Ray; Cysteine Endopeptidases; Esters; Kinetics; Models, Molecular; Molecular Structure; Protease Inhibitors; Triazoles; Viral Proteins