9ceh | pdb_00009ceh

SARS-CoV Papain-like Protease in complex with an inhibitor

spinqualitylabelsall models 9ceh, resolution 3.25Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9ceh is a 1 chain structure with sequence from Severe acute respiratory syndrome coronavirus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 3.25Å Ligands: A1AWG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function R1A_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. Publication Abstract from PubMed SARS-CoV-2 and -CoV viruses are major human pathogens. Due to their zoonotic nature as well as emerging drug-resistant mutations, new antivirals are needed. The viral papain-like protease (PLpro) is a drug target. Targeting the mostly hydrophobic S1' pocket of PLpro, we designed and synthesized 21 amide compounds, among which several highly potent PLpro inhibitors were identified with IC(50) values as low as 16 nM. Structure-activity relationship analysis showed that an electron-deficient pyridine-containing amide group can significantly enhance the activity. The X-ray structure of the PLpro-compound 15 complex revealed that the pyridine ring has favorable pi-pi and electrostatic interactions with the electron-rich indole group of Trp106. Compound 15 is inactive against human ubiquitin-specific protease 7 and noncytotoxic to mammalian cells, showing excellent selectivity. It can potently inhibit cellular replication of SARS-CoV-2 with an EC(50) of 96 nM. These results show that compound 15 represents a novel pharmaceutical lead for further drug development. Targeting the S1' Pocket of SARS-CoV‑2 Papain-Like Protease Yields Highly Potent Inhibitors.,Garad DN, Li X, Chua TK, Moku BK, Mishra CB, Song Y ACS Med Chem Lett. 2025 Oct 30;16(11):2280-2285. doi: , 10.1021/acsmedchemlett.5c00482. eCollection 2025 Nov 13. PMID:41256988 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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