5vmp | pdb_00005vmp

Crystal Structure of Human KDM4 with Small Molecule Inhibitor QC5714

spinqualitylabelsall models 5vmp, resolution 2.48Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5vmp is a 4 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 9FJ, NI, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [KDM4A_HUMAN] Histone demethylase that specifically demethylates 'Lys-9' and 'Lys-36' residues of histone H3, thereby playing a central role in histone code. Does not demethylate histone H3 'Lys-4', H3 'Lys-27' nor H4 'Lys-20'. Demethylates trimethylated H3 'Lys-9' and H3 'Lys-36' residue, while it has no activity on mono- and dimethylated residues. Demethylation of Lys residue generates formaldehyde and succinate. Participates in transcriptional repression of ASCL2 and E2F-responsive promoters via the recruitment of histone deacetylases and NCOR1, respectively. Isoform 2: Crucial for muscle differentiation, promotes transcriptional activation of the Myog gene by directing the removal of repressive chromatin marks at its promoter. Lacks the N-terminal demethylase domain. Publication Abstract from PubMed Histone lysine demethylases (KDMs) play a vital role in the regulation of chromatin-related processes. Herein, we describe our discovery of a series of potent KDM4 inhibitors that are both cell permeable and antiproliferative in cancer models. The modulation of histone H3K9me3 and H3K36me3 upon compound treatment was verified by homogeneous time-resolved fluorescence assay and by mass spectroscopy detection. Optimization of the series using structure-based drug design led to compound 6 (QC6352), a potent KDM4 family inhibitor that is efficacious in breast and colon cancer PDX models. Design of KDM4 Inhibitors with Antiproliferative Effects in Cancer Models.,Chen YK, Bonaldi T, Cuomo A, Del Rosario JR, Hosfield DJ, Kanouni T, Kao SC, Lai C, Lobo NA, Matuszkiewicz J, McGeehan A, O'Connell SM, Shi L, Stafford JA, Stansfield RK, Veal JM, Weiss MS, Yuen NY, Wallace MB ACS Med Chem Lett. 2017 Jul 27;8(8):869-874. doi: 10.1021/acsmedchemlett.7b00220., eCollection 2017 Aug 10. PMID:28835804 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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