View source for 9ggm


==Cryo-EM structure of KBTBD4 P313PRR mutant-HDAC2 2:2 complex==
<StructureSection load='9ggm' size='340' side='right'caption='[[9ggm]], [[Resolution|resolution]] 2.71&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9ggm]] is a 4 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=9GGM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9GGM 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]] 2.71&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ZN:ZINC+ION'>ZN</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=9ggm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9ggm OCA], [https://pdbe.org/9ggm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9ggm RCSB], [https://www.ebi.ac.uk/pdbsum/9ggm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9ggm ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/KBTB4_HUMAN KBTB4_HUMAN] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Neomorphic mutations and drugs can elicit unanticipated effects that require mechanistic understanding to inform clinical practice. Recurrent indel mutations in the Kelch domain of the KBTBD4 E3 ligase rewire epigenetic programs for stemness in medulloblastoma by recruiting LSD1-CoREST-HDAC1/2 complexes as neo-substrates for ubiquitination and degradation. UM171, an investigational drug for haematopoietic stem cell transplantation, was found to degrade LSD1-CoREST-HDAC1/2 complexes in a wild-type KBTBD4-dependent manner, suggesting a potential common mode of action. Here, we identify that these neomorphic interactions are mediated by the HDAC deacetylase domain. Cryo-EM studies of both wild-type and mutant KBTBD4 capture 2:1 and 2:2 KBTBD4-HDAC2 complexes, as well as a 2:1:1 KBTBD4-HDAC2-CoREST1 complex, at resolutions spanning 2.7 to 3.3 A. The mutant and drug-induced complexes adopt similar structural assemblies requiring both Kelch domains in the KBTBD4 dimer for each HDAC2 interaction. UM171 is identified as a bona fide molecular glue binding across the ternary interface. Most strikingly, the indel mutation reshapes the same surface of KBTBD4 providing an example of a natural mimic of a molecular glue. Together, the structures provide mechanistic understanding of neomorphic KBTBD4, while structure-activity relationship (SAR) analysis of UM171 reveals analog S234984 as a more potent molecular glue for future studies.

Structural mimicry of UM171 and neomorphic cancer mutants co-opts E3 ligase KBTBD4 for HDAC1/2 recruitment.,Chen Z, Chi G, Balo T, Chen X, Montes BR, Clifford SC, D'Angiolella V, Szabo T, Kiss A, Novak T, Herner A, Kotschy A, Bullock AN Nat Commun. 2025 Apr 2;16(1):3144. doi: 10.1038/s41467-025-58350-z. PMID:40175372<ref>PMID:40175372</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9ggm" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Bullock AN]]
[[Category: Chen Z]]
[[Category: Chi G]]
[[Category: Montes B]]
[[Category: Pike ACW]]