InterPro domain: IPR043504

This entry represents the chymotrypsin-like fold found in proteins from MEROPS peptidase family S1 (clan PA). The PA clan contains both cysteine and serine proteases that can be found in plants, animals, fungi, eubacteria, archaea and viruses [ 1 ].

The severe acute respiratory syndrome (SARS) 3C-like protease (3CL) consists of two distinct folds, namely the N-terminal chymotrypsin fold containing domains I and II, hosting the complete catalytic machinery and the C-terminal extra helical domain III, unique for the coronavirus 3CL proteases [ 2 ].

The structure of a 3CL, CoV M-pro, has been solved. It 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 [ 3 , 4 , 5 , 6 ]. Many drugs have been developed to inhibit CoV M-pro [ 7 ].

1. 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
2. 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
3. Structure of coronavirus main proteinase reveals combination of a chymotrypsin fold with an extra alpha-helical domain. EMBO J. 21, 3213-24
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