2v6n

Crystal structures of the SARS-coronavirus main proteinase inactivated by benzotriazole compounds

spinqualitylabelsall models 2v6n, resolution 1.98Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 2v6n is a 1 chain structure with sequence from Severe acute respiratory syndrome-related coronavirus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.98Å Ligands: MES, SO4, XP1 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function R1AB_SARS Multifunctional protein involved in the transcription and replication of viral RNAs. Contains the proteinases responsible for the cleavages of the polyprotein. Inhibits host translation by interacting with the 40S ribosomal subunit. The nsp1-40S ribosome complex further induces an endonucleolytic cleavage near the 5'UTR of host mRNAs, targeting them for degradation. Viral mRNAs are not susceptible to nsp1-mediated endonucleolytic RNA cleavage thanks to the presence of a 5'-end leader sequence and are therefore protected from degradation. By suppressing host gene expression, nsp1 facilitates efficient viral gene expression in infected cells and evasion from host immune response (PubMed:23035226). May disrupt nuclear pore function by binding and displacing host NUP93 (PubMed:30943371). May play a role in the modulation of host cell survival signaling pathway by interacting with host PHB and PHB2. Indeed, these two proteins play a role in maintaining the functional integrity of the mitochondria and protecting cells from various stresses. Responsible for the cleavages located at the N-terminus of the 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 (PubMed:17692280). Plays a role in host membrane rearrangement that leads to creation of cytoplasmic double-membrane vesicles (DMV) necessary for viral replication. Nsp3, nsp4 and nsp6 together are sufficient to form DMV (PubMed:24410069). Antagonizes innate immune induction of type I interferon by blocking the phosphorylation, dimerization and subsequent nuclear translocation of host IRF3 (PubMed:19369340, PubMed:24622840). Prevents also host NF-kappa-B signaling. Plays a role in host membrane rearrangement that leads to creation of cytoplasmic double-membrane vesicles (DMV) necessary for viral replication. Alone appears incapable to induce membrane curvature, but together with nsp3 is able to induce paired membranes. Nsp3, nsp4 and nsp6 together are sufficient to form DMV. Cleaves the C-terminus of replicase polyprotein at 11 sites. Recognizes substrates containing the core sequence [ILMVF]-Q-|-[SGACN]. Also able to bind an ADP-ribose-1-phosphate (ADRP). May cleave host ATP6V1G1 thereby modifying host vacuoles intracellular pH.[PROSITE-ProRule:PRU00772] Plays a role in host membrane rearrangement that leads to creation of cytoplasmic double-membrane vesicles (DMV) necessary for viral replication. Nsp3, nsp4 and nsp6 together are sufficient to form DMV (PubMed:24410069). Plays a role in the initial induction of autophagosomes from host reticulum endoplasmic. Later, limits the expansion of these phagosomes that are no longer able to deliver viral components to lysosomes (PubMed:24991833). Forms a hexadecamer with nsp8 (8 subunits of each) that may participate in viral replication by acting as a primase. Alternatively, may synthesize substantially longer products than oligonucleotide primers. Forms a hexadecamer with nsp7 (8 subunits of each) that may participate in viral replication by acting as a primase. Alternatively, may synthesize substantially longer products than oligonucleotide primers. May participate in viral replication by acting as a ssRNA-binding protein. Plays a pivotal role in viral transcription by stimulating both nsp14 3'-5' exoribonuclease and nsp16 2'-O-methyltransferase activities. Therefore plays an essential role in viral mRNAs cap methylation. Responsible for replication and transcription of the viral RNA genome. Multi-functional protein with a zinc-binding domain in N-terminus displaying RNA and DNA duplex-unwinding activities with 5' to 3' polarity. Activity of helicase is dependent on magnesium. Enzyme possessing two different activities: an exoribonuclease activity acting on both ssRNA and dsRNA in a 3' to 5' direction and a N7-guanine methyltransferase activity (PubMed:16549795, PubMed:20421945, PubMed:22635272). Acts as a proofreading exoribonuclease for RNA replication, thereby lowering The sensitivity of the virus to RNA mutagens (PubMed:23966862, PubMed:29511076, PubMed:21593585). Mn(2+)-dependent, uridylate-specific enzyme, which leaves 2'-3'-cyclic phosphates 5' to the cleaved bond. Methyltransferase that mediates mRNA cap 2'-O-ribose methylation to the 5'-cap structure of viral mRNAs. N7-methyl guanosine cap is a prerequisite for binding of nsp16. Therefore plays an essential role in viral mRNAs cap methylation which is essential to evade immune system. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed The main proteinase (M(pro)) of the severe acute respiratory syndrome (SARS) coronavirus is a principal target for the design of anticoronaviral compounds. Benzotriazole esters have been reported as potent nonpeptidic inhibitors of the enzyme, but their exact mechanism of action remains unclear. Here we present crystal structures of SARS-CoV M(pro), the active-site cysteine of which has been acylated by benzotriazole esters that act as suicide inhibitors. In one of the structures, the thioester product has been hydrolyzed and benzoic acid is observed to bind to the hydrophobic S2 pocket. This structure also features the enzyme with a shortened N-terminal segment ("amputated N finger"). The results further the understanding of the important role of the N finger for catalysis as well as the design of benzotriazole inhibitors with improved specificity. A structural view of the inactivation of the SARS coronavirus main proteinase by benzotriazole esters.,Verschueren KH, Pumpor K, Anemuller S, Chen S, Mesters JR, Hilgenfeld R Chem Biol. 2008 Jun;15(6):597-606. PMID:18559270 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also RNA-directed RNA polymerase

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