| Primary Identifier | IPR013016 | Type | Domain |
| Short Name | Peptidase_C16_CoV |
| description | This entry contains coronavirus (CoV) cysteine endopeptidases that belong to MEROPS peptidase family C16 (subfamilies C16A and C16B, clan CA). These peptidases are involved in viral polyprotein processing, releasing NSP1, NSP2 and NSP3 proteins []and they also function as deubiquitinating and deISG15ylating (interferon-induced gene 15) enzymes, disrupting host viral immune response to facilitate viral proliferation and replication. Therefore, this is an important target to develop antiviral treatments [].All coronaviruses encode between one and two accessory cysteine proteinases that recognise and process one or three sites in the amino-terminal half of the replicase polyprotein during assembly of the viral replication complex. MHV, HCoV and TGEV encode two accessory proteinases, called coronavirus papain-like proteinase 1 and 2 (PL1-PRO and PL2-PRO) []. IBV and SARS encodes only one called PL-PRO (PL2-PRO, conserved in all CoVs) [, , ]. The structures of both PL-PROs are similar and they also have restricted specificities. The PL1-PRO of TGEV cleaves the polyprotein between Nsp2-Nsp3 recognising the Lys-Met-Gly-Gly motif, and recognises Leu-Arg-Gly-Gly in ubiquitin (ub) which shows that it is able to accommodate residues as different as Lys and Leu. In contrast, PL-PRO from SARS-CoV recognises Leu-Xaa-Gly-Gly (Xaa could be any amino acid) and cleaves peptide bonds between Nsp1-Nsp2, Nsp2-Nsp3 and between Nsp3-Nsp4 [, , ]. In Ub and ISG15 proteins, it recognises Leu-Arg-Gly-Gly motifs. SARS-CoV and SARS-CoV-2 are closely related but exhibit different host substrate preferences: SARS-CoV-2 PL-PRO preferentially cleaves the ubiquitin-like ISG15, whereas SARS-CoV PL-PRO predominantly targets ubiquitin chains [, ].The peptidase family C16 domain is about 260 amino acids in length and the solved structures determined that it consists of thumb, palm, and fingers subdomains. The thumb is comprised of six α-helices and a small β-hairpin; the fingers subdomain is made of six β-strands and two α-helices and includes a zinc binding site, in which the zinc ion is coordinated by four cysteine residues. Zinc binding is essential for structural integrity and protease activity, with a conformation that varies most between different PL-PRO structures. The palm subdomain is comprised of six β-strands and includes the catalytic residues Cys-His-Asp, located at the interface between the thumb and palm subdomains []. |
