5VAR
Crystal structure of KDM4A tandem TUDOR domain in complex with a tri-methyl lysine competitive inhibitor
Summary for 5VAR
| Entry DOI | 10.2210/pdb5var/pdb |
| Descriptor | Lysine-specific demethylase 4A, (1R,2S,3R,4S)-3-[(dimethylamino)methyl]-1-phenylbicyclo[2.2.1]heptan-2-ol (3 entities in total) |
| Functional Keywords | kdm4a tandem tudor domain, oxidoreductase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 13788.26 |
| Authors | Judge, R.A.,Upadhyay, A.K. (deposition date: 2017-03-27, release date: 2018-03-28, Last modification date: 2023-10-04) |
| Primary citation | Upadhyay, A.K.,Judge, R.A.,Li, L.,Pithawalla, R.,Simanis, J.,Bodelle, P.M.,Marin, V.L.,Henry, R.F.,Petros, A.M.,Sun, C. Targeting lysine specific demethylase 4A (KDM4A) tandem TUDOR domain - A fragment based approach. Bioorg. Med. Chem. Lett., 28:1708-1713, 2018 Cited by PubMed Abstract: The tandem TUDOR domains present in the non-catalytic C-terminal half of the KDM4A, 4B and 4C enzymes play important roles in regulating their chromatin localizations and substrate specificities. They achieve this regulatory role by binding to different tri-methylated lysine residues on histone H3 (H3-K4me3, H3-K23me3) and histone H4 (H4-K20me3) depending upon the specific chromatin environment. In this work, we have used a 2D-NMR based fragment screening approach to identify a novel fragment (1a), which binds to the KDM4A-TUDOR domain and shows modest competition with H3-K4me3 binding in biochemical as well as in vitro cell based assays. A co-crystal structure of KDM4A TUDOR domain in complex with 1a shows that the fragment binds stereo-specifically to the methyl lysine binding pocket forming a network of strong hydrogen bonds and hydrophobic interactions. We anticipate that the fragment 1a can be further developed into a novel allosteric inhibitor of the KDM4 family of enzymes through targeting their C-terminal tandem TUDOR domain. PubMed: 29691138DOI: 10.1016/j.bmcl.2018.04.050 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.83 Å) |
Structure validation
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