7DYX
Human JMJD5 in complex with MN and 5-((2-cyclopropylbenzyl)amino)pyridine-2,4-dicarboxylic acid.
Summary for 7DYX
| Entry DOI | 10.2210/pdb7dyx/pdb |
| Descriptor | Bifunctional peptidase and arginyl-hydroxylase JMJD5, MANGANESE (II) ION, 5-((2-cyclopropylbenzyl)amino)pyridine-2,4-dicarboxylic acid, ... (4 entities in total) |
| Functional Keywords | jmjc domain-containing protein 5, jmjd5, dioxygenase, oxidoreductase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 27629.13 |
| Authors | Nakashima, Y.,Brewitz, L.,Schofield, C.J. (deposition date: 2021-01-23, release date: 2022-02-02, Last modification date: 2023-12-06) |
| Primary citation | Brewitz, L.,Nakashima, Y.,Piasecka, S.K.,Salah, E.,Fletcher, S.C.,Tumber, A.,Corner, T.P.,Kennedy, T.J.,Fiorini, G.,Thalhammer, A.,Christensen, K.E.,Coleman, M.L.,Schofield, C.J. 5-Substituted Pyridine-2,4-dicarboxylate Derivatives Have Potential for Selective Inhibition of Human Jumonji-C Domain-Containing Protein 5. J.Med.Chem., 66:10849-10865, 2023 Cited by PubMed Abstract: Jumonji-C domain-containing protein 5 (JMJD5) is a 2-oxoglutarate (2OG)-dependent oxygenase that plays important roles in development, circadian rhythm, and cancer through unclear mechanisms. JMJD5 has been reported to have activity as a histone protease, as an -methyl lysine demethylase, and as an arginine residue hydroxylase. Small-molecule JMJD5-selective inhibitors will be useful for investigating its (patho)physiological roles. Following the observation that the broad-spectrum 2OG oxygenase inhibitor pyridine-2,4-dicarboxylic acid (2,4-PDCA) is a 2OG-competing JMJD5 inhibitor, we report that 5-aminoalkyl-substituted 2,4-PDCA derivatives are potent JMJD5 inhibitors manifesting selectivity for JMJD5 over other human 2OG oxygenases. Crystallographic analyses with five inhibitors imply induced fit binding and reveal that the 2,4-PDCA C5 substituent orients into the JMJD5 substrate-binding pocket. Cellular studies indicate that the lead compounds display similar phenotypes as reported for clinically observed JMJD5 variants, which have a reduced catalytic activity compared to wild-type JMJD5. PubMed: 37527664DOI: 10.1021/acs.jmedchem.3c01114 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.27 Å) |
Structure validation
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