7CAJ

Crystal structure of SETDB1 Tudor domain in complexed with Compound 2.

Summary for 7CAJ

• Entry DOI: 10.2210/pdb7caj/pdb
• Descriptor: Histone-lysine N-methyltransferase SETDB1, 3-methyl-2-[[(3R,5R)-1-methyl-5-phenyl-piperidin-3-yl]amino]-5H-pyrrolo[3,2-d]pyrimidin-4-one (3 entities in total)
• Functional Keywords: epigenetic, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 55901.94

Authors

Guo, Y.P.,Liang, X.,Xin, M.,Luyi, H.,Chengyong, W.,Yang, S.Y. (deposition date: 2020-06-08, release date: 2021-04-07, Last modification date: 2023-11-29)

Primary citation

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., 60:8760-8765, 2021

PubMed Abstract: 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 K value of 0.088±0.045 μM 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.

PubMed: 33511756
DOI: 10.1002/anie.202017200

Experimental method

X-RAY DIFFRACTION (2.198 Å)