6ett
Crystal structure of KDM4D with tetrazole compound 4
Structural highlights
FunctionKDM4D_HUMAN Histone demethylase that specifically demethylates 'Lys-9' of histone H3, thereby playing a central role in histone code. Does not demethylate histone H3 'Lys-4', H3 'Lys-27', H3 'Lys-36' nor H4 'Lys-20'. Demethylates both di- and trimethylated H3 'Lys-9' residue, while it has no activity on monomethylated residues. Demethylation of Lys residue generates formaldehyde and succinate.[1] Publication Abstract from PubMedHuman histone demethylases are known to play an important role in the development of several tumor types. Consequently, they have emerged as important medical targets for the treatment of human cancer. Herein, structural studies on tetrazolylhydrazide inhibitors as a new scaffold for a certain class of histone demethylases, the JmjC proteins, are reported. A series of compounds are structurally described and their respective binding modes to the KDM4D protein, which serves as a high-resolution model to represent the KDM4 subfamily in crystallographic studies, are examined. Similar to previously reported inhibitors, the compounds described herein are competitors for the natural KDM4 cofactor, 2-oxoglutarate. The tetrazolylhydrazide scaffold fills an important gap in KDM4 inhibition and newly described, detailed interactions of inhibitor moieties pave the way to the development of compounds with high target-binding affinity and increased membrane permeability, at the same time. Structure-Based Screening of Tetrazolylhydrazide Inhibitors versus KDM4 Histone Demethylases.,Malecki PH, Ruger N, Roatsch M, Krylova O, Link A, Jung M, Heinemann U, Weiss MS ChemMedChem. 2019 Nov 6;14(21):1828-1839. doi: 10.1002/cmdc.201900441. Epub 2019 , Oct 10. PMID:31475772[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
| ||||||||||||||||||||
