9rme: Difference between revisions

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'''Unreleased structure'''


The entry 9rme is ON HOLD until Paper Publication
==Hybrid NMR/Xray structure of SARS-CoV2 macrodomain (nsp3b) in complex with the sulfamoyl derivative of GS-441524==
<StructureSection load='9rme' size='340' side='right'caption='[[9rme]]' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9rme]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Severe_acute_respiratory_syndrome_coronavirus Severe acute respiratory syndrome coronavirus]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9RME OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9RME FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR,  models</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1JHT:[(2~{R},3~{S},4~{R},5~{R})-5-(4-azanylpyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-bis(oxidanyl)oxolan-2-yl]methyl+sulfamate'>A1JHT</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=9rme FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9rme OCA], [https://pdbe.org/9rme PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9rme RCSB], [https://www.ebi.ac.uk/pdbsum/9rme PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9rme 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 ==
Viral macrodomains, which hydrolyze mono-ADP-ribosylated proteins to evade host immunity, represent emerging antiviral targets, yet their druggability remains underexplored. GS-441524, the active metabolite of remdesivir, has been identified as an inhibitor of the SARS-CoV-2 (severe acute respiratory syndrome coronavirus) macrodomain (Nsp3b). Herein, the structure-activity relationship governing macrodomain recognition by the ribosylated moiety using a panel of nucleoside analogs, revealing that phosphate configuration and nucleobase identity critically modulate binding affinity. GS-441524 derivatives exhibit up to 200-fold higher affinity compared to adenosine-based ligands. A novel sulfamoyl derivative demonstrates superior inhibitory potency, attributable to its occupation of the phosphate subsite and formation of a stabilizing hydrogen-bond network. These findings provide molecular insights into Nsp3b-ligand interactions and establish a rational framework for the development of high-affinity, structure-guided inhibitors targeting viral macrodomains.


Authors: Mineev, K.S., Krishnathas, R., Gande, S.L., Linhard, V., Tsika, A., Sideras-Bisdekis, C., Fourkiotis, N., Lennartz, F., Spyroulias, G., Weiss, M., Sreeramulu, S., Schwalbe, H.
Structure-Based Rational Design of a Selective Hydrolase Inhibitor of the Severe Acute Respiratory Syndrome Coronavirus-2 Nsp3 Macrodomain.,Krishnathas R, Mineev KS, Fourkiotis NK, Touret F, Sideras-Bisdekis C, Tsika AC, Gande SL, Linhard V, Sreeramulu S, Lennartz F, Weiss MS, Coutard B, Spyroulias GA, Schwalbe H Chembiochem. 2025 Nov 27;26(23):e202500593. doi: 10.1002/cbic.202500593. Epub , 2025 Nov 2. PMID:41176653<ref>PMID:41176653</ref>


Description: Hybrid NMR/Xray structure of SARS-CoV2 macrodomain (nsp3b) in complex with the sulfamoyl derivative of GS-441524
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[Category: Unreleased Structures]]
</div>
[[Category: Krishnathas, R]]
<div class="pdbe-citations 9rme" style="background-color:#fffaf0;"></div>
[[Category: Spyroulias, G]]
== References ==
[[Category: Tsika, A]]
<references/>
[[Category: Gande, S.L]]
__TOC__
[[Category: Sreeramulu, S]]
</StructureSection>
[[Category: Linhard, V]]
[[Category: Large Structures]]
[[Category: Lennartz, F]]
[[Category: Severe acute respiratory syndrome coronavirus]]
[[Category: Schwalbe, H]]
[[Category: Fourkiotis N]]
[[Category: Mineev, K.S]]
[[Category: Gande SL]]
[[Category: Fourkiotis, N]]
[[Category: Krishnathas R]]
[[Category: Weiss, M]]
[[Category: Lennartz F]]
[[Category: Sideras-Bisdekis, C]]
[[Category: Linhard V]]
[[Category: Mineev KS]]
[[Category: Schwalbe H]]
[[Category: Sideras-Bisdekis C]]
[[Category: Spyroulias G]]
[[Category: Sreeramulu S]]
[[Category: Tsika A]]
[[Category: Weiss M]]