View source for 9fkr


==KAT6A IN COMPLEX WITH SMALL MOLECULE INHIBITOR BAY-184==
<StructureSection load='9fkr' size='340' side='right'caption='[[9fkr]], [[Resolution|resolution]] 2.69&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9fkr]] is a 2 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=9FKR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9FKR 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]] 2.69&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1IDR:6-(dimethylamino)-~{N}-(2-phenylphenyl)sulfonyl-1-benzofuran-2-carboxamide'>A1IDR</scene>, <scene name='pdbligand=ALY:N(6)-ACETYLLYSINE'>ALY</scene>, <scene name='pdbligand=EPE:4-(2-HYDROXYETHYL)-1-PIPERAZINE+ETHANESULFONIC+ACID'>EPE</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=9fkr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9fkr OCA], [https://pdbe.org/9fkr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9fkr RCSB], [https://www.ebi.ac.uk/pdbsum/9fkr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9fkr ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/KAT6A_HUMAN KAT6A_HUMAN] Note=Chromosomal aberrations involving KAT6A may be a cause of acute myeloid leukemias. Translocation t(8;16)(p11;p13) with CREBBP; translocation t(8;22)(p11;q13) with EP300. KAT6A-CREBBP may induce leukemia by inhibiting RUNX1-mediated transcription. Inversion inv(8)(p11;q13) generates the KAT6A-NCOA2 oncogene, which consists of the N-terminal part of KAT6A and the C-terminal part of NCOA2/TIF2. KAT6A-NCOA2 binds to CREBBP and disrupts its function in transcription activation.  Note=A chromosomal aberration involving KAT6A is a cause of therapy-related myelodysplastic syndrome. Translocation t(2;8)(p23;p11.2) with ASXL2 generates a KAT6A-ASXL2 fusion protein.
== Function ==
[https://www.uniprot.org/uniprot/KAT6A_HUMAN KAT6A_HUMAN] Histone acetyltransferase that acetylates lysine residues in histone H3 and histone H4 (in vitro). Component of the MOZ/MORF complex which has a histone H3 acetyltransferase activity. May act as a transcriptional coactivator for RUNX1 and RUNX2.<ref>PMID:11742995</ref> <ref>PMID:11965546</ref> <ref>PMID:12771199</ref> <ref>PMID:16387653</ref> <ref>PMID:17925393</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
KAT6A and KAT6B genes are two closely related lysine acetyltransferases that transfer an acetyl group from acetyl coenzyme A (AcCoA) to lysine residues of target histone substrates, hence playing a key role in chromatin regulation. KAT6A and KAT6B genes are frequently amplified in various cancer types. In breast cancer, the 8p11-p12 amplicon occurs in 12-15% of cases, resulting in elevated copy numbers and expression levels of chromatin modifiers like KAT6A. Here, we report the discovery of a new acylsulfonamide-benzofuran series as a novel structural class for KAT6A/B inhibition. These compounds were identified through high-throughput screening and subsequently optimized using molecular modeling and cocrystal structure determination. The final tool compound, BAY-184 (29), was successfully validated in an in vivo proof-of-concept study.

Discovery and Characterization of BAY-184: A New Potent and Selective Acylsulfonamide-Benzofuran In Vivo-Active KAT6AB Inhibitor.,Ter Laak A, Hillig RC, Ferrara SJ, Korr D, Barak N, Lienau P, Herbert S, Fernandez-Montalvan AE, Neuhaus R, Gorjanacz M, Puetter V, Badock V, Bone W, Strathdee C, Siegel F, Schatz C, Nowak-Reppel K, Doehr O, Gradl S, Hartung IV, Meyerson M, Bouche L J Med Chem. 2024 Oct 25. doi: 10.1021/acs.jmedchem.4c01709. PMID:39450890<ref>PMID:39450890</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9fkr" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Hillig RC]]
[[Category: Puetter V]]