View source for 9ggl


==Cryo-EM structure of KBTBD4 WT-HDAC2 2:1 complex mediated by molecular glue UM171==
<StructureSection load='9ggl' size='340' side='right'caption='[[9ggl]], [[Resolution|resolution]] 3.13&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9ggl]] is a 3 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=9GGL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9GGL 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]] 3.13&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1ACV:~{N}4-[7-(2-methyl-1,2,3,4-tetrazol-5-yl)-2-(phenylmethyl)-9~{H}-pyrimido[4,5-b]indol-4-yl]cyclohexane-1,4-diamine'>A1ACV</scene>, <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=9ggl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9ggl OCA], [https://pdbe.org/9ggl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9ggl RCSB], [https://www.ebi.ac.uk/pdbsum/9ggl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9ggl ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/HDAC2_HUMAN HDAC2_HUMAN] Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Forms transcriptional repressor complexes by associating with MAD, SIN3, YY1 and N-COR. Interacts in the late S-phase of DNA-replication with DNMT1 in the other transcriptional repressor complex composed of DNMT1, DMAP1, PCNA, CAF1. Deacetylates TSHZ3 and regulates its transcriptional repressor activity. Component of a RCOR/GFI/KDM1A/HDAC complex that suppresses, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development.<ref>PMID:19343227</ref> 
<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 9ggl" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Bullock AN]]
[[Category: Chen Z]]
[[Category: Chi G]]
[[Category: Montes B]]
[[Category: Pike ACW]]