6au2 | pdb_00006au2

Crystal structure of SETDB1 Tudor domain with aryl triazole fragments

Structural highlights

6au2 is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	BME, CGJ, EDO, SO4, UNX
Gene:	SETDB1, KIAA0067, KMT1E (HUMAN)
Activity:	Histone-lysine N-methyltransferase, with EC number 2.1.1.43
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 human histone-lysine methyltransferase which is amplified in human cancers and was shown to be crucial in the growth of non-small and small cell lung carcinoma. In addition to its catalytic domain, SETDB1 harbors a unique tandem tudor domain which recognizes histone sequences containing both methylated and acetylated lysines, and likely contributes to its localization on chromatin. Using X-ray crystallography and NMR spectroscopy fragment screening approaches, we have identified the first small molecule fragment hits that bind to histone peptide binding groove of the Tandem Tudor Domain (TTD) of SETDB1. Herein, we describe the binding modes of these fragments and analogues and the biophysical characterization of key compounds. These confirmed small molecule fragments will inform the development of potent antagonists of SETDB1 interaction with histones.

Identification and characterization of the first fragment hits for SETDB1 Tudor domain.,Mader P, Mendoza-Sanchez R, Iqbal A, Dong A, Dobrovetsky E, Corless VB, Liew SK, Houliston SR, De Freitas RF, Smil D, Sena CCD, Kennedy S, Diaz DB, Wu H, Dombrovski L, Allali-Hassani A, Min J, Schapira M, Vedadi M, Brown PJ, Santhakumar V, Yudin AK, Arrowsmith CH Bioorg Med Chem. 2019 Sep 1;27(17):3866-3878. doi: 10.1016/j.bmc.2019.07.020., Epub 2019 Jul 12. PMID:31327677^[5]

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

References

↑ 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:https://dx.doi.org/10.1101/gad.1102803
↑ 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
↑ 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:https://dx.doi.org/10.1016/j.molcel.2004.06.043
↑ 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:https://dx.doi.org/10.1038/ncb1647
↑ Mader P, Mendoza-Sanchez R, Iqbal A, Dong A, Dobrovetsky E, Corless VB, Liew SK, Houliston SR, De Freitas RF, Smil D, Sena CCD, Kennedy S, Diaz DB, Wu H, Dombrovski L, Allali-Hassani A, Min J, Schapira M, Vedadi M, Brown PJ, Santhakumar V, Yudin AK, Arrowsmith CH. Identification and characterization of the first fragment hits for SETDB1 Tudor domain. Bioorg Med Chem. 2019 Sep 1;27(17):3866-3878. doi: 10.1016/j.bmc.2019.07.020., Epub 2019 Jul 12. PMID:31327677 doi:https://dx.doi.org/10.1016/j.bmc.2019.07.020

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OCA

[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:https://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:https://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:https://dx.doi.org/10.1038/ncb1647

[5] Mader P, Mendoza-Sanchez R, Iqbal A, Dong A, Dobrovetsky E, Corless VB, Liew SK, Houliston SR, De Freitas RF, Smil D, Sena CCD, Kennedy S, Diaz DB, Wu H, Dombrovski L, Allali-Hassani A, Min J, Schapira M, Vedadi M, Brown PJ, Santhakumar V, Yudin AK, Arrowsmith CH. Identification and characterization of the first fragment hits for SETDB1 Tudor domain. Bioorg Med Chem. 2019 Sep 1;27(17):3866-3878. doi: 10.1016/j.bmc.2019.07.020., Epub 2019 Jul 12. PMID:31327677 doi:https://dx.doi.org/10.1016/j.bmc.2019.07.020

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6au2 | pdb_00006au2

Crystal structure of SETDB1 Tudor domain with aryl triazole fragments

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

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