7cjt

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==Crystal Structure of SETDB1 Tudor domain in complexed with (R,R)-59==
==Crystal Structure of SETDB1 Tudor domain in complexed with (R,R)-59==
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<StructureSection load='7cjt' size='340' side='right'caption='[[7cjt]]' scene=''>
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<StructureSection load='7cjt' size='340' side='right'caption='[[7cjt]], [[Resolution|resolution]] 2.47&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7CJT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7CJT FirstGlance]. <br>
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<table><tr><td colspan='2'>[[7cjt]] 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=7CJT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7CJT FirstGlance]. <br>
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</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=7cjt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7cjt OCA], [https://pdbe.org/7cjt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7cjt RCSB], [https://www.ebi.ac.uk/pdbsum/7cjt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7cjt ProSAT]</span></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.474&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=G09:2-[[(3~{R},5~{R})-1-methyl-5-(4-phenylmethoxyphenyl)piperidin-3-yl]amino]-3-prop-2-enyl-5~{H}-pyrrolo[3,2-d]pyrimidin-4-one'>G09</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7cjt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7cjt OCA], [https://pdbe.org/7cjt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7cjt RCSB], [https://www.ebi.ac.uk/pdbsum/7cjt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7cjt ProSAT]</span></td></tr>
</table>
</table>
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== Function ==
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[https://www.uniprot.org/uniprot/SETB1_HUMAN SETB1_HUMAN] Histone methyltransferase that specifically trimethylates 'Lys-9' of histone H3. H3 'Lys-9' trimethylation represents a specific tag for epigenetic transcriptional repression by recruiting HP1 (CBX1, CBX3 and/or CBX5) proteins to methylated histones. Mainly functions in euchromatin regions, thereby playing a central role in the silencing of euchromatic genes. H3 'Lys-9' trimethylation is coordinated with DNA methylation. Probably forms a complex with MBD1 and ATF7IP that represses transcription and couples DNA methylation and histone 'Lys-9' trimethylation. Its activity is dependent on MBD1 and is heritably maintained through DNA replication by being recruited by CAF-1. SETDB1 is targeted to histone H3 by TRIM28/TIF1B, a factor recruited by KRAB zinc-finger proteins.<ref>PMID:12869583</ref> <ref>PMID:14536086</ref> <ref>PMID:15327775</ref> <ref>PMID:17952062</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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SET domain bifurcated protein 1 (SETDB1) is a histone lysine methyltransferase that promotes the silencing of some tumour suppressor genes and is overexpressed in many cancers. SETDB1 contains a unique tandem tudor domain (TTD) that recognizes histone H3 sequences containing both methylated and acetylated lysines. Beginning with the identification of a hit compound (Cpd1), we discovered the first potent and selective small molecule SETDB1-TTD inhibitor (R,R)-59 through stepwise structure-guided optimization. (R,R)-59 showed a KD value of 0.088+/-0.045 muM in the ITC assay. The high potency of (R,R)-59 was well explained by the cocrystal structure of the (R,R)-59-TTD complex. (R,R)-59 is an endogenous binder competitive inhibitor. Evidence has also demonstrated its cellular target engagement. Interestingly, the enantiomer (S,S)-59 did not show activity in all the assays, highlighting the potential of (R,R)-59 as a tool compound in exploring the biological functions of SETDB1-TTD.
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Structure-Guided Discovery of a Potent and Selective Cell-Active Inhibitor of SETDB1 Tudor Domain.,Guo Y, Mao X, Xiong L, Xia A, You J, Lin G, Wu C, Huang L, Wang Y, Yang S Angew Chem Int Ed Engl. 2021 Apr 12;60(16):8760-8765. doi:, 10.1002/anie.202017200. Epub 2021 Mar 8. PMID:33511756<ref>PMID:33511756</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 7cjt" style="background-color:#fffaf0;"></div>
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==See Also==
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*[[Histone methyltransferase 3D structures|Histone methyltransferase 3D structures]]
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== References ==
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<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Guo YP]]
[[Category: Guo YP]]

Current revision

Crystal Structure of SETDB1 Tudor domain in complexed with (R,R)-59

PDB ID 7cjt

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