View source for 7kxi


==Structure of XL5-ligated hRpn13 Pru domain==
<StructureSection load='7kxi' size='340' side='right'caption='[[7kxi]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7kxi]] is a 1 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7KXI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7KXI FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=XAY:2-{[(2S)-2-cyano-3-{3-[(4-methylbenzene-1-carbonyl)amino]phenyl}propanoyl]amino}benzoic+acid'>XAY</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=7kxi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7kxi OCA], [https://pdbe.org/7kxi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7kxi RCSB], [https://www.ebi.ac.uk/pdbsum/7kxi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7kxi ProSAT]</span></td></tr>
</table>
== Function ==
[[https://www.uniprot.org/uniprot/ADRM1_HUMAN ADRM1_HUMAN]] Functions as a proteasomal ubiquitin receptor. Recruits the deubiquitinating enzyme UCHL5 at the 26S proteasome and promotes its activity.<ref>PMID:16990800</ref> <ref>PMID:17139257</ref> <ref>PMID:16815440</ref> <ref>PMID:16906146</ref> <ref>PMID:18497817</ref>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Proteasome substrate receptor hRpn13 is a promising anti-cancer target. By integrated in silico and biophysical screening, we identified a chemical scaffold that binds hRpn13 with non-covalent interactions that mimic the proteasome and a weak electrophile for Michael addition. hRpn13 Pru domain binds proteasomes and ubiquitin whereas its DEUBAD domain binds deubiquitinating enzyme UCHL5. NMR revealed lead compound XL5 to interdigitate into a hydrophobic pocket created by lateral movement of a Pru beta-hairpin with an exposed end for Proteolysis Targeting Chimeras (PROTACs). Implementing XL5-PROTACs as chemical probes identified a DEUBAD-lacking hRpn13 species (hRpn13(Pru)) present naturally with cell type-dependent abundance. XL5-PROTACs preferentially target hRpn13(Pru), causing its ubiquitination. Gene-editing and rescue experiments established hRpn13 requirement for XL5-PROTAC-triggered apoptosis. These data establish hRpn13 as an anti-cancer target for multiple myeloma and introduce an hRpn13-targeting scaffold that can be optimized for preclinical trials against hRpn13(Pru)-producing cancer types.

Structure-guided bifunctional molecules hit a DEUBAD-lacking hRpn13 species upregulated in multiple myeloma.,Lu X, Sabbasani VR, Osei-Amponsa V, Evans CN, King JC, Tarasov SG, Dyba M, Das S, Chan KC, Schwieters CD, Choudhari S, Fromont C, Zhao Y, Tran B, Chen X, Matsuo H, Andresson T, Chari R, Swenson RE, Tarasova NI, Walters KJ Nat Commun. 2021 Dec 16;12(1):7318. doi: 10.1038/s41467-021-27570-4. PMID:34916494<ref>PMID:34916494</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7kxi" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Lu, X]]
[[Category: Walters, K J]]
[[Category: Complex]]
[[Category: Protein binding]]