View source for 9xg0


==Structure of SARS-CoV-2 Mpro complexed with 4bf==
<StructureSection load='9xg0' size='340' side='right'caption='[[9xg0]], [[Resolution|resolution]] 2.21&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9xg0]] is a 1 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=9XG0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9XG0 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]] 2.21&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1MCJ:1-[(2~{S},4~{S})-6-bromanyl-1-ethanoyl-2-(3,4,5-trimethoxyphenyl)-3,4-dihydro-2~{H}-quinolin-4-yl]pyrrolidin-2-one'>A1MCJ</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=9xg0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9xg0 OCA], [https://pdbe.org/9xg0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9xg0 RCSB], [https://www.ebi.ac.uk/pdbsum/9xg0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9xg0 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/R1AB_SARS2 R1AB_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] (PubMed:32198291). Also able to bind an ADP-ribose-1''-phosphate (ADRP).[UniProtKB:P0C6X7]<ref>PMID:32198291</ref>   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]  Responsible for replication and transcription of the viral RNA genome.[UniProtKB:P0C6X7]  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.[UniProtKB:P0C6X7]  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. Acts as a proofreading exoribonuclease for RNA replication, thereby lowering The sensitivity of the virus to RNA mutagens.[UniProtKB:P0C6X7]  Mn(2+)-dependent, uridylate-specific enzyme, which leaves 2'-3'-cyclic phosphates 5' to the cleaved bond.[UniProtKB:P0C6X7]  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.[UniProtKB:P0C6X7]
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== Publication Abstract from PubMed ==
This study presents the design, synthesis, and evaluation of a novel series of covalent broad-spectrum inhibitors targeting the coronavirus main protease (3CLpro). The designed compounds feature a tetrahydroquinoline (THQ) scaffold functionalized with a chloroacetamide warhead. The most potent of this series in the primary screening assay, 4bf and 5bf, exhibited low micromolar IC(5)(0) values against 3CLpro of SARS-CoV-2, SARS-CoV, and MERS-CoV, thereby demonstrating significant cross-reactivity. Structural analysis via X-ray crystallography confirmed covalent binding to the catalytic Cys145 residue. Complementary molecular dynamics simulations revealed stable binding modes and key interactions, highlighting differences in flexibility and residue contacts between the top inhibitors. While in vitro cytotoxicity was observed in Vero E6 cells, acute toxicity studies in mice revealed an LD(5)(0) exceeding 1000 mg/kg for the lead compounds, indicating a promising in vivo safety profile. These findings establish substituted tetrahydroquinolines as a viable scaffold for the development of broad-spectrum anticoronaviral agents.

Design, synthesis, and structural characterization of covalent tetrahydroquinoline-based inhibitors of coronavirus 3CLpro.,Pronina AA, Shcherbakov DN, Sanchez-Pimentel AP, Nikitina EV, Zubkov FI, Meshkova YV, Marenina MK, Maltsev NV, Belenkaya SV, Trufanov VO, Volosnikova EA, Zaykovskay AV, Borisevich SS, Khamitov EM, Baev DS, Mustaev EA, Fedorov AY, Arkhipov SG, Vlaskina AV, Nemchinova AR, Samygina VR, Pyankov OV, Yarovaya O, Xu W, Salakhutdinov NF, Khvostov MV Bioorg Chem. 2026 Oct 5;181:110402. doi: 10.1016/j.bioorg.2026.110402. Epub 2026 , Aug 31. PMID:42673845<ref>PMID:42673845</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
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== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Severe acute respiratory syndrome coronavirus 2]]
[[Category: Namchinova AR]]
[[Category: Samygina VR]]
[[Category: Vlaskina AV]]