InterPro domain: IPR043477

This group of cysteine peptidases correspond to MEROPS peptidase family C30 (clan PA(C)). These peptidases are related to serine endopeptidases of family S1 and are restricted to RNA viruses, where they are involved in viral polyprotein processing during replication [ 1 , 2 , 3 ].

This Coronavirus (CoV) domain, peptidase C30, is also known as 3C-like proteinase (3CL-pro), or CoV main protease (M-pro) domain. CoV M-pro is a dimer where each subunit is composed of three domains I, II and III. Domains I and II consist of six-stranded antiparallel beta barrels and together resemble the architecture of chymotrypsin, and of picornaviruses 3C proteinases. The substrate-binding site is located in a cleft between these two domains. The catalytic site is situated at the centre of the cleft. A long loop connects domain II to the C-terminal domain (domain III). This latter domain, a globular cluster of five helices, has been implicated in the proteolytic activity of M-pro. In the active site of M-pro, Cys and His form a catalytic dyad. In contrast to serine proteinases and other cysteine proteinases, which have a catalytic triad, there is no third catalytic residue present [ 4 , 4 , 5 , 6 ]. Many drugs have been developed to inhibit CoV M-pro [ 7 ].

This superfamily represents CoV M-pro domain III, which is reported to be required for dimerisation [ 8 ]. Whereas the chymotrypsin-like fold formed by domains I and II is also present in MEROPS family S1 peptidases found in plants, animals, fungi, eubacteria, archaea and viruses, the C-terminal extra helical domain III is unique for the coronavirus 3CL proteases [ 9 , 10 ].

1. Structure of coronavirus main proteinase reveals combination of a chymotrypsin fold with an extra alpha-helical domain. EMBO J. 21, 3213-24
2. Virus-encoded proteinases and proteolytic processing in the Nidovirales. J. Gen. Virol. 81, 853-79
3. Conservation of substrate specificities among coronavirus main proteases. J. Gen. Virol. 83, 595-9
4. Coronavirus main proteinase (3CLpro) structure: basis for design of anti-SARS drugs. Science 300, 1763-7
5. Structures of two coronavirus main proteases: implications for substrate binding and antiviral drug design. J. Virol. 82, 2515-27
6. Structure of the main protease from a global infectious human coronavirus, HCoV-HKU1. J. Virol. 82, 8647-55
7. Picornaviral 3C protease inhibitors and the dual 3C protease/coronaviral 3C-like protease inhibitors. Expert Opin Ther Pat 20, 59-71
8. Dissection study on the severe acute respiratory syndrome 3C-like protease reveals the critical role of the extra domain in dimerization of the enzyme: defining the extra domain as a new target for design of highly specific protease inhibitors. J. Biol. Chem. 279, 24765-73
9. Viral cysteine proteases are homologous to the trypsin-like family of serine proteases: structural and functional implications. Proc. Natl. Acad. Sci. U.S.A. 85, 7872-6