cd21732

betacoronavirus papain-like protease

CDD entry
Member databaseCDD
CDD typedomain
Short namebetaCoV_PLPro
SetCoV_PLPro

Description

This model represents the papain-like protease (PLPro) found in non-structural protein 3 (Nsp3) of betacoronavirus, including highly pathogenic betacoronaviruses such as Severe acute respiratory syndrome-related coronavirus (SARS-CoV), SARS-CoV2 (also called 2019 novel CoV or 2019-nCoV), and Middle East respiratory syndrome-related (MERS) CoV. CoVs utilize a multi-subunit replication/transcription machinery. A set of non-structural proteins (Nsps) generated as cleavage products of the ORF1a and ORF1ab viral polyproteins assemble to facilitate viral replication and transcription. PLPro is a key enzyme in this process, making it a high value target for the development of anti-coronavirus therapeutics. PLPro, which belongs to the MEROPS peptidase C16 family, participates in the proteolytic processing of the N-terminal region of the replicase polyprotein; it can cleave Nsp1|Nsp2, Nsp2|Nsp3, and Nsp3|Nsp4 sites and its activity is dependent on zinc. In SARS-CoV and murine hepatitis virus (MHV), the C-terminal non-structural protein 3 region spanning transmembrane regions TM1 and TM2 with 3Ecto domain in between, are important for the PL2pro domain to process Nsp3-Nsp4 cleavage. Besides cleaving the polyproteins, PLPro also possesses a related enzymatic activity to promote virus replication: deubiquitinating (DUB) and de-ISGylating activities. Both, ubiquitin (Ub) and Ub-like interferon-stimulated gene product 15 (ISG15), are involved in preventing viral infection; coronaviruses utilize Ubl-conjugating pathways to counter the pro-inflammatory properties of Ubl-conjugated host proteins via the action of PLPro, which processes both 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains from cellular substrates. The Nsp3 PLPro domain of many of these CoVs has also been shown to antagonize host innate immune induction of type I interferon by interacting with IRF3 and blocking its activation. Interactions of SARS-CoV and MERS-CoV with antiviral interferon (IFN) responses of human cells are remarkably different; high-dose IFN treatment (type I and type III) shows MERS-CoV was substantially more IFN sensitive than SARS-CoV. This may be due to differences in the architecture of the oxyanion hole and of the S3 as well as the S5 specificity sites, despite the overall structures of SARS-CoV and MERS-CoV PLPro being similar.
[2, 9, 10, 8, 1, 4, 11, 7, 14, 13, 3, 15, 5, 6, 16, 12]

References

1.Recognition of Lys48-Linked Di-ubiquitin and Deubiquitinating Activities of the SARS Coronavirus Papain-like Protease. Bekes M, van der Heden van Noort GJ, Ekkebus R, Ovaa H, Huang TT, Lima CD. Mol Cell 62, 572-85, (2016). PMID: 27203180

2.Severe acute respiratory syndrome coronavirus papain-like protease: structure of a viral deubiquitinating enzyme. Ratia K, Saikatendu KS, Santarsiero BD, Barretto N, Baker SC, Stevens RC, Mesecar AD. Proc. Natl. Acad. Sci. U.S.A. 103, 5717-22, (2006). View articlePMID: 16581910

3.Crystal structure of the Middle East respiratory syndrome coronavirus (MERS-CoV) papain-like protease bound to ubiquitin facilitates targeted disruption of deubiquitinating activity to demonstrate its role in innate immune suppression. Bailey-Elkin BA, Knaap RC, Johnson GG, Dalebout TJ, Ninaber DK, van Kasteren PB, Bredenbeek PJ, Snijder EJ, Kikkert M, Mark BL. J. Biol. Chem. 289, 34667-82, (2014). PMID: 25320088

4.Structural and mutational analysis of the interaction between the Middle-East respiratory syndrome coronavirus (MERS-CoV) papain-like protease and human ubiquitin. Lei J, Hilgenfeld R. Virol Sin 31, 288-99, (2016). PMID: 27245450

5.Interaction of SARS and MERS Coronaviruses with the Antiviral Interferon Response. Kindler E, Thiel V, Weber F. Adv Virus Res 96, 219-243, (2016). PMID: 27712625

6.Deubiquitinating and interferon antagonism activities of coronavirus papain-like proteases. Clementz MA, Chen Z, Banach BS, Wang Y, Sun L, Ratia K, Baez-Santos YM, Wang J, Takayama J, Ghosh AK, Li K, Mesecar AD, Baker SC. J Virol 84, 4619-29, (2010). PMID: 20181693

7.Structural basis for catalysis and ubiquitin recognition by the severe acute respiratory syndrome coronavirus papain-like protease. Chou CY, Lai HY, Chen HY, Cheng SC, Cheng KW, Chou YW. Acta Crystallogr D Biol Crystallogr 70, 572-81, (2014). PMID: 24531491

8.Disulfiram can inhibit MERS and SARS coronavirus papain-like proteases via different modes. Lin MH, Moses DC, Hsieh CH, Cheng SC, Chen YH, Sun CY, Chou CY. Antiviral Res 150, 155-163, (2018). PMID: 29289665

9.Structural Insights into the Interaction of Coronavirus Papain-Like Proteases and Interferon-Stimulated Gene Product 15 from Different Species. Daczkowski CM, Dzimianski JV, Clasman JR, Goodwin O, Mesecar AD, Pegan SD. J Mol Biol 429, 1661-1683, (2017). PMID: 28438633

10.Structurally Guided Removal of DeISGylase Biochemical Activity from Papain-Like Protease Originating from Middle East Respiratory Syndrome Coronavirus. Daczkowski CM, Goodwin OY, Dzimianski JV, Farhat JJ, Pegan SD. J Virol 91, e01067-17, (2017). PMID: 28931677

11.X-ray Structural and Functional Studies of the Three Tandemly Linked Domains of Non-structural Protein 3 (nsp3) from Murine Hepatitis Virus Reveal Conserved Functions. Chen Y, Savinov SN, Mielech AM, Cao T, Baker SC, Mesecar AD. J Biol Chem 290, 25293-306, (2015). PMID: 26296883

12.Regulation of IRF-3-dependent innate immunity by the papain-like protease domain of the severe acute respiratory syndrome coronavirus. Devaraj SG, Wang N, Chen Z, Chen Z, Tseng M, Barretto N, Lin R, Peters CJ, Tseng CT, Baker SC, Li K. J Biol Chem 282, 32208-21, (2007). PMID: 17761676

13.Crystal structure of the papain-like protease of MERS coronavirus reveals unusual, potentially druggable active-site features. Lei J, Mesters JR, Drosten C, Anemuller S, Ma Q, Hilgenfeld R. Antiviral Res 109, 72-82, (2014). PMID: 24992731

14.X-ray structural and biological evaluation of a series of potent and highly selective inhibitors of human coronavirus papain-like proteases. Baez-Santos YM, Barraza SJ, Wilson MW, Agius MP, Mielech AM, Davis NM, Baker SC, Larsen SD, Mesecar AD. J Med Chem 57, 2393-412, (2014). PMID: 24568342

15.Severe acute respiratory syndrome coronavirus papain-like novel protease inhibitors: design, synthesis, protein-ligand X-ray structure and biological evaluation. Ghosh AK, Takayama J, Rao KV, Ratia K, Chaudhuri R, Mulhearn DC, Lee H, Nichols DB, Baliji S, Baker SC, Johnson ME, Mesecar AD. J. Med. Chem. 53, 4968-79, (2010). View articlePMID: 20527968

16.Coronavirus papain-like proteases negatively regulate antiviral innate immune response through disruption of STING-mediated signaling. Sun L, Xing Y, Chen X, Zheng Y, Yang Y, Nichols DB, Clementz MA, Banach BS, Li K, Baker SC, Chen Z. PLoS One 7, e30802, (2012). PMID: 22312431

This website requires cookies, and the limited processing of your personal data in order to function. By using the site you are agreeing to this as outlined in our Privacy Notice and Terms of Use.