7cjt

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

Structural highlights

7cjt is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.474Å
Ligands:G09
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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.[1] [2] [3] [4]

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[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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See Also

References

  1. ↑ Ayyanathan K, Lechner MS, Bell P, Maul GG, Schultz DC, Yamada Y, Tanaka K, Torigoe K, Rauscher FJ 3rd. Regulated recruitment of HP1 to a euchromatic gene induces mitotically heritable, epigenetic gene silencing: a mammalian cell culture model of gene variegation. Genes Dev. 2003 Aug 1;17(15):1855-69. Epub 2003 Jul 17. PMID:12869583 doi:http://dx.doi.org/10.1101/gad.1102803
  2. ↑ Wang H, An W, Cao R, Xia L, Erdjument-Bromage H, Chatton B, Tempst P, Roeder RG, Zhang Y. mAM facilitates conversion by ESET of dimethyl to trimethyl lysine 9 of histone H3 to cause transcriptional repression. Mol Cell. 2003 Aug;12(2):475-87. PMID:14536086
  3. ↑ Sarraf SA, Stancheva I. Methyl-CpG binding protein MBD1 couples histone H3 methylation at lysine 9 by SETDB1 to DNA replication and chromatin assembly. Mol Cell. 2004 Aug 27;15(4):595-605. PMID:15327775 doi:http://dx.doi.org/10.1016/j.molcel.2004.06.043
  4. ↑ Takada I, Mihara M, Suzawa M, Ohtake F, Kobayashi S, Igarashi M, Youn MY, Takeyama K, Nakamura T, Mezaki Y, Takezawa S, Yogiashi Y, Kitagawa H, Yamada G, Takada S, Minami Y, Shibuya H, Matsumoto K, Kato S. A histone lysine methyltransferase activated by non-canonical Wnt signalling suppresses PPAR-gamma transactivation. Nat Cell Biol. 2007 Nov;9(11):1273-85. Epub 2007 Oct 21. PMID:17952062 doi:http://dx.doi.org/10.1038/ncb1647
  5. ↑ Guo Y, Mao X, Xiong L, Xia A, You J, Lin G, Wu C, Huang L, Wang Y, Yang S. Structure-Guided Discovery of a Potent and Selective Cell-Active Inhibitor of SETDB1 Tudor Domain. Angew Chem Int Ed Engl. 2021 Apr 12;60(16):8760-8765. doi:, 10.1002/anie.202017200. Epub 2021 Mar 8. PMID:33511756 doi:http://dx.doi.org/10.1002/anie.202017200

Contents


PDB ID 7cjt

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OCA

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