6fuk
From Proteopedia
Crystal structure of UTX complexed with 5-carboxy-8-hydroxyquinoline
Structural highlights
Disease[KDM6A_HUMAN] Kabuki syndrome. The disease is caused by mutations affecting the gene represented in this entry. Function[KDM6A_HUMAN] Histone demethylase that specifically demethylates 'Lys-27' of histone H3, thereby playing a central role in histone code. Demethylates trimethylated and dimethylated but not monomethylated H3 'Lys-27'. Plays a central role in regulation of posterior development, by regulating HOX gene expression. Demethylation of 'Lys-27' of histone H3 is concomitant with methylation of 'Lys-4' of histone H3, and regulates the recruitment of the PRC1 complex and monoubiquitination of histone H2A.[1] [2] Publication Abstract from PubMedIn the search for new demethylase inhibitors, we have developed a multistep protocol for in silico screening. Millions of poses generated by high-throughput docking or a 3D-pharmacophore search are first minimized by a classical force field and then filtered by semiempirical quantum mechanical calculations of the interaction energy with a selected set of functional groups in the binding site. The final ranking includes solvation effects which are evaluated in the continuum dielectric approximation (finite-difference Poisson equation). Application of the multistep protocol to JMJD3 jumonji demethylase has resulted in a dozen low-micromolar inhibitors belonging to five different chemical classes. We have solved the crystal structure of JMJD3 inhibitor 8 in the complex with UTX (a demethylase in the same subfamily as JMJD3) which validates the predicted binding mode. Compound 8 is a promising candidate for future optimization as it has a favorable ligand efficiency of 0.32 kcal/mol per nonhydrogen atom. In Silico Identification of JMJD3 Demethylase Inhibitors.,Esposito C, Wiedmer L, Caflisch A J Chem Inf Model. 2018 Oct 3. doi: 10.1021/acs.jcim.8b00539. PMID:30226987[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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