8okc: Difference between revisions
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New page: '''Unreleased structure''' The entry 8okc is ON HOLD Authors: Calderone, V. Description: SARS-CoV2 NSP5 in complex with PROTAC Category: Unreleased Structures [[Category: Calderone... |
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==SARS-CoV2 NSP5 in complex with a GC-376 based peptidomimetic PROTAC== | |||
<StructureSection load='8okc' size='340' side='right'caption='[[8okc]], [[Resolution|resolution]] 2.00Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[8okc]] 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=8OKC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8OKC 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]] 2Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=VQN:(phenylmethyl)+~{N}-[(2~{R})-1-[[(~{Z},2~{S})-5-[4-[[1-[2-[(3~{R})-2,6-bis(oxidanylidene)piperidin-3-yl]-6-fluoranyl-1,3-bis(oxidanylidene)isoindol-5-yl]piperidin-4-yl]methyl]piperazin-1-yl]-5-oxidanylidene-1-[(3~{R})-2-oxidanylidenepyrrolidin-3-yl]pent-3-en-2-yl]amino]-4-methyl-1-oxidanylidene-pentan-2-yl]carbamate'>VQN</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=8okc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8okc OCA], [https://pdbe.org/8okc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8okc RCSB], [https://www.ebi.ac.uk/pdbsum/8okc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8okc ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
We have applied a proteolysis targeting chimera (PROTAC) technology to obtain a peptidomimetic molecule able to trigger the degradation of SARS-CoV-2 3-chymotrypsin-like protease (3CL(Pro)). The PROTAC molecule was designed by conjugating a GC-376 based dipeptidyl 3CL(Pro) ligand to a pomalidomide moiety through a piperazine-piperidine linker. NMR and crystallographic data complemented with enzymatic and cellular studies showed that (i) the dipeptidyl moiety of PROTAC binds to the active site of the dimeric state of SARS-CoV-2 3CL(Pro) forming a reversible covalent bond with the sulfur atom of catalytic Cys145, (ii) the linker and the pomalidomide cereblon-ligand of PROTAC protrude from the protein, displaying a high degree of flexibility and no interactions with other regions of the protein, and (iii) PROTAC reduces the protein levels of SARS-CoV-2 3CL(Pro) in cultured cells. This study paves the way for the future applicability of peptidomimetic PROTACs to tackle 3CL(Pro)-dependent viral infections. | |||
Development of a GC-376 Based Peptidomimetic PROTAC as a Degrader of 3-Chymotrypsin-like Protease of SARS-CoV-2.,Grifagni D, Lenci E, De Santis A, Orsetti A, Barracchia CG, Tedesco F, Bellini Puglielli R, Lucarelli F, Lauriola A, Assfalg M, Cantini F, Calderone V, Guardavaccaro D, Trabocchi A, D'Onofrio M, Ciofi-Baffoni S ACS Med Chem Lett. 2024 Jan 10;15(2):250-257. doi: , 10.1021/acsmedchemlett.3c00498. eCollection 2024 Feb 8. PMID:38352832<ref>PMID:38352832</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: Calderone | <div class="pdbe-citations 8okc" style="background-color:#fffaf0;"></div> | ||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Severe acute respiratory syndrome coronavirus 2]] | |||
[[Category: Calderone V]] | |||
Latest revision as of 09:57, 9 October 2024
SARS-CoV2 NSP5 in complex with a GC-376 based peptidomimetic PROTAC
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