3U78

E67-2 selectively inhibits KIAA1718, a human histone H3 lysine 9 Jumonji demethylase

Summary for 3U78

• Entry DOI: 10.2210/pdb3u78/pdb
• Related: 3KVA
• Descriptor: Lysine-specific demethylase 7, 2-OXOGLUTARIC ACID, NICKEL (II) ION, ... (8 entities in total)
• Functional Keywords: epigenetics, histone lysine demethylation, bix analogs, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus: Q6ZMT4
• Total number of polymer chains: 1
• Total formula weight: 47091.24

Authors

Upadhyay, A.K.,Cheng, X. (deposition date: 2011-10-13, release date: 2012-01-25, Last modification date: 2023-09-13)

Primary citation

Upadhyay, A.K.,Rotili, D.,Han, J.W.,Hu, R.,Chang, Y.,Labella, D.,Zhang, X.,Yoon, Y.S.,Mai, A.,Cheng, X.
An Analog of BIX-01294 Selectively Inhibits a Family of Histone H3 Lysine 9 Jumonji Demethylases.
J.Mol.Biol., 416:319-327, 2012

PubMed Abstract: BIX-01294 and its analogs were originally identified and subsequently designed as potent inhibitors against histone H3 lysine 9 (H3K9) methyltransferases G9a and G9a-like protein. Here, we show that BIX-01294 and its analog E67 can also inhibit H3K9 Jumonji demethylase KIAA1718 with half-maximal inhibitory concentrations in low micromolar range. Crystallographic analysis of KIAA1718 Jumonji domain in complex with E67 indicated that the benzylated six-membered piperidine ring was disordered and exposed to solvent. Removing the moiety (generating compound E67-2) has no effect on the potency against KIAA1718 but, unexpectedly, lost inhibition against G9a-like protein by a factor of 1500. Furthermore, E67 and E67-2 have no effect on the activity against histone H3 lysine 4 (H3K4) demethylase JARID1C. Thus, our study provides a new avenue for designing and improving the potency and selectivity of inhibitors against H3K9 Jumonji demethylases over H3K9 methyltransferases and H3K4 demethylases.

PubMed: 22227394
DOI: 10.1016/j.jmb.2011.12.036

Experimental method

X-RAY DIFFRACTION (2.689 Å)