Proteopedia

3aw0

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Structure of SARS 3CL protease with peptidic aldehyde inhibitorStructure of SARS 3CL protease with peptidic aldehyde inhibitor

Structural highlights

3aw0 is a 2 chain structure with sequence from Cvhsa. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
NonStd Res:,
Gene:1a (CVHSA)
Activity:SARS coronavirus main proteinase, with EC number 3.4.22.69
Resources:FirstGlance, OCA, RCSB, PDBsum

Function

[R1A_CVHSA] The papain-like proteinase (PL-PRO) is responsible for the cleavages located at the N-terminus of replicase polyprotein. In addition, PL-PRO possesses a deubiquitinating/deISGylating activity and processes both 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains from cellular substrates. Antagonizes innate immune induction of type I interferon by blocking the phosphorylation, dimerization and subsequent nuclear translocation of host IRF-3.[1] [2] [3] The main proteinase 3CL-PRO is responsible for the majority of cleavages as it cleaves the C-terminus of replicase polyprotein at 11 sites. Recognizes substrates containing the core sequence [ILMVF]-Q-|-[SGACN]. Inhibited by the substrate-analog Cbz-Val-Asn-Ser-Thr-Leu-Gln-CMK (By similarity). Also contains an ADP-ribose-1-phosphate (ADRP)-binding function.[4] [5] [6] Nsp7-nsp8 hexadecamer may possibly confer processivity to the polymerase, maybe by binding to dsRNA or by producing primers utilized by the latter.[7] [8] [9] Nsp9 is a ssRNA-binding protein.[10] [11] [12]

Publication Abstract from PubMed

The design and evaluation of low molecular weight peptide-based severe acute respiratory syndrome (SARS) chymotrypsin-like protease (3CL) protease inhibitors are described. A substrate-based peptide aldehyde was selected as a starting compound, and optimum side-chain structures were determined, based on a comparison of inhibitory activities with Michael type inhibitors. For the efficient screening of peptide aldehydes containing a specific C-terminal residue, a new approach employing thioacetal to aldehyde conversion mediated by N-bromosuccinimide was devised. Structural optimization was carried out based on X-ray crystallographic analyses of the R188I SARS 3CL protease in a complex with each inhibitor to provide a tetrapeptide aldehyde with an IC(50) value of 98 nM. The resulting compound carried no substrate sequence, except for a P(3) site directed toward the outside of the protease. X-ray crystallography provided insights into the protein-ligand interactions.

Structure-Based Design, Synthesis, and Evaluation of Peptide-Mimetic SARS 3CL Protease Inhibitors.,Akaji K, Konno H, Mitsui H, Teruya K, Shimamoto Y, Hattori Y, Ozaki T, Kusunoki M, Sanjoh A J Med Chem. 2011 Dec 8;54(23):7962-73. Epub 2011 Nov 9. PMID:22014094[13]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ Imbert I, Guillemot JC, Bourhis JM, Bussetta C, Coutard B, Egloff MP, Ferron F, Gorbalenya AE, Canard B. A second, non-canonical RNA-dependent RNA polymerase in SARS coronavirus. EMBO J. 2006 Oct 18;25(20):4933-42. Epub 2006 Oct 5. PMID:17024178 doi:7601368
  2. ↑ Lindner HA, Lytvyn V, Qi H, Lachance P, Ziomek E, Menard R. Selectivity in ISG15 and ubiquitin recognition by the SARS coronavirus papain-like protease. Arch Biochem Biophys. 2007 Oct 1;466(1):8-14. Epub 2007 Jul 14. PMID:17692280 doi:10.1016/j.abb.2007.07.006
  3. ↑ Frieman M, Ratia K, Johnston RE, Mesecar AD, Baric RS. Severe acute respiratory syndrome coronavirus papain-like protease ubiquitin-like domain and catalytic domain regulate antagonism of IRF3 and NF-kappaB signaling. J Virol. 2009 Jul;83(13):6689-705. doi: 10.1128/JVI.02220-08. Epub 2009 Apr 15. PMID:19369340 doi:10.1128/JVI.02220-08
  4. ↑ Imbert I, Guillemot JC, Bourhis JM, Bussetta C, Coutard B, Egloff MP, Ferron F, Gorbalenya AE, Canard B. A second, non-canonical RNA-dependent RNA polymerase in SARS coronavirus. EMBO J. 2006 Oct 18;25(20):4933-42. Epub 2006 Oct 5. PMID:17024178 doi:7601368
  5. ↑ Lindner HA, Lytvyn V, Qi H, Lachance P, Ziomek E, Menard R. Selectivity in ISG15 and ubiquitin recognition by the SARS coronavirus papain-like protease. Arch Biochem Biophys. 2007 Oct 1;466(1):8-14. Epub 2007 Jul 14. PMID:17692280 doi:10.1016/j.abb.2007.07.006
  6. ↑ Frieman M, Ratia K, Johnston RE, Mesecar AD, Baric RS. Severe acute respiratory syndrome coronavirus papain-like protease ubiquitin-like domain and catalytic domain regulate antagonism of IRF3 and NF-kappaB signaling. J Virol. 2009 Jul;83(13):6689-705. doi: 10.1128/JVI.02220-08. Epub 2009 Apr 15. PMID:19369340 doi:10.1128/JVI.02220-08
  7. ↑ Imbert I, Guillemot JC, Bourhis JM, Bussetta C, Coutard B, Egloff MP, Ferron F, Gorbalenya AE, Canard B. A second, non-canonical RNA-dependent RNA polymerase in SARS coronavirus. EMBO J. 2006 Oct 18;25(20):4933-42. Epub 2006 Oct 5. PMID:17024178 doi:7601368
  8. ↑ Lindner HA, Lytvyn V, Qi H, Lachance P, Ziomek E, Menard R. Selectivity in ISG15 and ubiquitin recognition by the SARS coronavirus papain-like protease. Arch Biochem Biophys. 2007 Oct 1;466(1):8-14. Epub 2007 Jul 14. PMID:17692280 doi:10.1016/j.abb.2007.07.006
  9. ↑ Frieman M, Ratia K, Johnston RE, Mesecar AD, Baric RS. Severe acute respiratory syndrome coronavirus papain-like protease ubiquitin-like domain and catalytic domain regulate antagonism of IRF3 and NF-kappaB signaling. J Virol. 2009 Jul;83(13):6689-705. doi: 10.1128/JVI.02220-08. Epub 2009 Apr 15. PMID:19369340 doi:10.1128/JVI.02220-08
  10. ↑ Imbert I, Guillemot JC, Bourhis JM, Bussetta C, Coutard B, Egloff MP, Ferron F, Gorbalenya AE, Canard B. A second, non-canonical RNA-dependent RNA polymerase in SARS coronavirus. EMBO J. 2006 Oct 18;25(20):4933-42. Epub 2006 Oct 5. PMID:17024178 doi:7601368
  11. ↑ Lindner HA, Lytvyn V, Qi H, Lachance P, Ziomek E, Menard R. Selectivity in ISG15 and ubiquitin recognition by the SARS coronavirus papain-like protease. Arch Biochem Biophys. 2007 Oct 1;466(1):8-14. Epub 2007 Jul 14. PMID:17692280 doi:10.1016/j.abb.2007.07.006
  12. ↑ Frieman M, Ratia K, Johnston RE, Mesecar AD, Baric RS. Severe acute respiratory syndrome coronavirus papain-like protease ubiquitin-like domain and catalytic domain regulate antagonism of IRF3 and NF-kappaB signaling. J Virol. 2009 Jul;83(13):6689-705. doi: 10.1128/JVI.02220-08. Epub 2009 Apr 15. PMID:19369340 doi:10.1128/JVI.02220-08
  13. ↑ Akaji K, Konno H, Mitsui H, Teruya K, Shimamoto Y, Hattori Y, Ozaki T, Kusunoki M, Sanjoh A. Structure-Based Design, Synthesis, and Evaluation of Peptide-Mimetic SARS 3CL Protease Inhibitors. J Med Chem. 2011 Dec 8;54(23):7962-73. Epub 2011 Nov 9. PMID:22014094 doi:10.1021/jm200870n

3aw0, resolution 2.30Å

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