Like many viruses, SARS-CoV2 synthesizes its proteins in long, polypeptide chains that must be cleaved to form functional proteins. SARS-CoV2 uses two different proteases, a papain-like protease and the main protease. [1] While papain-like protease(s) cleave only three sites, the main protease cleaves 11 sites in the polyprotein to generate functional proteins, and is the focus of this page.
Overall Structure and Active Site of M protease
The main protease is a cysteine protease that is essential for the viral life cycle. It is forms a consisting of the perpendicular protomers A and B. One protomer consists of . Domains I and II form an antiparallel chymotrypsin-like ß-barrel structure. Domain III (C-terminal end) consist of five alpha-helices arranged in an antiparallel cluster. [2] [3] The substrate binds in a between Domains I and II. Most of the residues in the channel are neutral (shown in white) with a few acidic residues. S1 is the and consists of the side chains Phe 140, His 163 and the backbone atoms of Glu166, Asn142, Gly 143 and His172. It confers absolute specificity for the Gln-P1 substrate residue on the enzyme as the carbonyl oxygen of Gln-P1 is stabilized by an which is formed by amide groups of Gly143 and the catalytic Cys145. [4] [5] Hence, polyproteins are cleaved within the Leu-Gln↓(Ser, Ala, Gly) sequence. [6]
The active site involves a consisting of the residues Cys145 and His41. It forms a covalent intermediate with the substrate in a similar fashion to serine proteases.
Peptidic inhibitors
A number of structures of MPro with candidate inhibitors have been determined, including , , , , , and 6WTT.
