9t0r: Difference between revisions
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==Crystal structure of SARS-CoV-2 Mpro in complex with GK729== | |||
<StructureSection load='9t0r' size='340' side='right'caption='[[9t0r]], [[Resolution|resolution]] 1.55Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[9t0r]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Severe_acute_respiratory_syndrome_coronavirus_2 Severe acute respiratory syndrome coronavirus 2]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9T0R OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9T0R FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.55Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1JSW:(phenylmethyl)+~{N}-[(2~{S})-1-[[(1~{S},2~{S})-1-[4-(1-methoxyethenyl)-1,3-thiazol-2-yl]-1-oxidanyl-3-[(3~{S})-2-oxidanylidenepyrrolidin-3-yl]propan-2-yl]amino]-4-methyl-1-oxidanylidene-pentan-2-yl]carbamate'>A1JSW</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=9t0r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9t0r OCA], [https://pdbe.org/9t0r PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9t0r RCSB], [https://www.ebi.ac.uk/pdbsum/9t0r PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9t0r ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/R1A_SARS2 R1A_SARS2] Multifunctional protein involved in the transcription and replication of viral RNAs. Contains the proteinases responsible for the cleavages of the polyprotein.[UniProtKB:P0C6X7] 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.[UniProtKB:P0C6X7] 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.[UniProtKB:P0C6X7] 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. Participates together with nsp4 in the assembly of virally-induced cytoplasmic double-membrane vesicles necessary for viral replication. Antagonizes innate immune induction of type I interferon by blocking the phosphorylation, dimerization and subsequent nuclear translocation of host IRF3. Prevents also host NF-kappa-B signaling.[UniProtKB:P0C6X7] Participates in the assembly of virally-induced cytoplasmic double-membrane vesicles necessary for viral replication.[UniProtKB:P0C6X7] 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).[UniProtKB:P0C6X7] 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.[UniProtKB:P0C6X7] 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.[UniProtKB:P0C6X7] 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.[UniProtKB:P0C6X7] May participate in viral replication by acting as a ssRNA-binding protein.[UniProtKB:P0C6X7] 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.[UniProtKB:P0C6X7] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The SARS-CoV-2 main protease (M(pro)), an enzyme essential for viral replication and lacking a human homologue, has emerged as a highly attractive target for the development of novel antiviral agents. Although several M(pro) inhibitors have been developed - some receiving regulatory approval - their use is sometimes limited by drug-drug interactions. In this study, we designed and synthesized peptidomimetic SARS-CoV-2 M(pro) inhibitors incorporating a novel thiazolyl 4-carboxylate ketone warhead, previously employed by our group in the development of cytosolic phospholipase A(2) inhibitors. The synthesized compounds were evaluated for their in vitro inhibitory potency against SARS-CoV-2 M(pro), and a highly potent M(pro) inhibitor (GK730) was identified (IC(50) 5.75 nM). The melting temperature of the M(pro)-GK730 complex revealed high stability, consistent with the high inhibitory potency. The X-ray crystal structures of inhibitors GK729 and GK730 bound to M(pro) were determined, providing insights into the binding interactions and mechanism of action. Studies on the host cell proteases cathepsin B and L showed that GK730 did not inhibit cathepsin B, while exhibited weak inhibition of cathepsin L. Furthermore, GK730 demonstrated an EC(50) value of 5.70 muM against a wild-type SARS-CoV-2 strain in Vero E6 cells and minimal cytotoxicity (CC(50) value greater than 100 muM). | |||
Thiazolyl 4-carboxylate ketone as a new warhead for a highly potent SARS-CoV-2 main protease inhibitor.,Theodoropoulou MA, El Kilani H, Mantzourani C, Jochmans D, Neyts J, Zhang K, Roske J, Kokotou MG, Hilgenfeld R, Kokotos G Eur J Med Chem. 2026 Feb 5;303:118436. doi: 10.1016/j.ejmech.2025.118436. Epub , 2025 Nov 29. PMID:41344111<ref>PMID:41344111</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 9t0r" style="background-color:#fffaf0;"></div> | ||
[[Category: El Kilani | == References == | ||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Severe acute respiratory syndrome coronavirus 2]] | |||
[[Category: El Kilani H]] | |||
[[Category: Hilgenfeld R]] | |||
