7uih: Difference between revisions
New page: '''Unreleased structure''' The entry 7uih is ON HOLD Authors: Description: Category: Unreleased Structures |
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The | ==PSMD2 Structure== | ||
<StructureSection load='7uih' size='340' side='right'caption='[[7uih]], [[Resolution|resolution]] 3.10Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[7uih]] is a 5 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7UIH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7UIH FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.1Å</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=7uih FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7uih OCA], [https://pdbe.org/7uih PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7uih RCSB], [https://www.ebi.ac.uk/pdbsum/7uih PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7uih ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Engineered destruction of target proteins by recruitment to the cell's degradation machinery has emerged as a promising strategy in drug discovery. The majority of molecules that facilitate targeted degradation do so via a select number of ubiquitin ligases, restricting this therapeutic approach to tissue types that express the requisite ligase. Here, we describe a new strategy of targeted protein degradation through direct substrate recruitment to the 26S proteasome. The proteolytic complex is essential and abundantly expressed in all cells; however, proteasomal ligands remain scarce. We identify potent peptidic macrocycles that bind directly to the 26S proteasome subunit PSMD2, with a 2.5-A-resolution cryo-electron microscopy complex structure revealing a binding site near the 26S pore. Conjugation of this macrocycle to a potent BRD4 ligand enabled generation of chimeric molecules that effectively degrade BRD4 in cells, thus demonstrating that degradation via direct proteasomal recruitment is a viable strategy for targeted protein degradation. | |||
Targeted degradation via direct 26S proteasome recruitment.,Bashore C, Prakash S, Johnson MC, Conrad RJ, Kekessie IA, Scales SJ, Ishisoko N, Kleinheinz T, Liu PS, Popovych N, Wecksler AT, Zhou L, Tam C, Zilberleyb I, Srinivasan R, Blake RA, Song A, Staben ST, Zhang Y, Arnott D, Fairbrother WJ, Foster SA, Wertz IE, Ciferri C, Dueber EC Nat Chem Biol. 2023 Jan;19(1):55-63. doi: 10.1038/s41589-022-01218-w. Epub 2022 , Dec 28. PMID:36577875<ref>PMID:36577875</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 7uih" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Bashore C]] | |||
[[Category: Ciferri C]] | |||
[[Category: Dueber EC]] | |||
[[Category: Johnson MC]] | |||
Latest revision as of 08:12, 12 June 2024
PSMD2 StructurePSMD2 Structure
Structural highlights
Publication Abstract from PubMedEngineered destruction of target proteins by recruitment to the cell's degradation machinery has emerged as a promising strategy in drug discovery. The majority of molecules that facilitate targeted degradation do so via a select number of ubiquitin ligases, restricting this therapeutic approach to tissue types that express the requisite ligase. Here, we describe a new strategy of targeted protein degradation through direct substrate recruitment to the 26S proteasome. The proteolytic complex is essential and abundantly expressed in all cells; however, proteasomal ligands remain scarce. We identify potent peptidic macrocycles that bind directly to the 26S proteasome subunit PSMD2, with a 2.5-A-resolution cryo-electron microscopy complex structure revealing a binding site near the 26S pore. Conjugation of this macrocycle to a potent BRD4 ligand enabled generation of chimeric molecules that effectively degrade BRD4 in cells, thus demonstrating that degradation via direct proteasomal recruitment is a viable strategy for targeted protein degradation. Targeted degradation via direct 26S proteasome recruitment.,Bashore C, Prakash S, Johnson MC, Conrad RJ, Kekessie IA, Scales SJ, Ishisoko N, Kleinheinz T, Liu PS, Popovych N, Wecksler AT, Zhou L, Tam C, Zilberleyb I, Srinivasan R, Blake RA, Song A, Staben ST, Zhang Y, Arnott D, Fairbrother WJ, Foster SA, Wertz IE, Ciferri C, Dueber EC Nat Chem Biol. 2023 Jan;19(1):55-63. doi: 10.1038/s41589-022-01218-w. Epub 2022 , Dec 28. PMID:36577875[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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