7c9n
From Proteopedia
(Difference between revisions)
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==Crystal structure of SETDB1 tudor domain in complexed with Compound 1.== | ==Crystal structure of SETDB1 tudor domain in complexed with Compound 1.== | ||
| - | <StructureSection load='7c9n' size='340' side='right'caption='[[7c9n]]' scene=''> | + | <StructureSection load='7c9n' size='340' side='right'caption='[[7c9n]], [[Resolution|resolution]] 2.47Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7C9N OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7C9N FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7c9n]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7C9N OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7C9N FirstGlance]. <br> |
| - | </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=7c9n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7c9n OCA], [https://pdbe.org/7c9n PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7c9n RCSB], [https://www.ebi.ac.uk/pdbsum/7c9n PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7c9n ProSAT]</span></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FN9:3,5-dimethyl-2-[[(3R,5R)-1-methyl-5-phenyl-piperidin-3-yl]amino]pyrrolo[3,2-d]pyrimidin-4-one'>FN9</scene></td></tr> |
| + | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">SETDB1, ESET, KIAA0067, KMT1E ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=7c9n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7c9n OCA], [https://pdbe.org/7c9n PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7c9n RCSB], [https://www.ebi.ac.uk/pdbsum/7c9n PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7c9n ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | == Function == | ||
| + | [[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> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | 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. | ||
| + | |||
| + | 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> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 7c9n" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[Category: Human]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| - | [[Category: Guo Y]] | + | [[Category: Guo, Y]] |
| - | [[Category: Mao X]] | + | [[Category: Mao, X]] |
| - | [[Category: Xiong L]] | + | [[Category: Xiong, L]] |
| - | [[Category: Yang S]] | + | [[Category: Yang, S]] |
| + | [[Category: Gene regulation-inhibitor complex]] | ||
Revision as of 07:01, 14 April 2021
Crystal structure of SETDB1 tudor domain in complexed with Compound 1.
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