4ER5

Crystal structure of human DOT1L in complex with 2 molecules of EPZ004777

4ER5 の概要

• エントリーDOI: 10.2210/pdb4er5/pdb
• 関連するPDBエントリー: 4EQZ 4ER0 4ER3 4ER6 4ER7
• 分子名称: Histone-lysine N-methyltransferase, H3 lysine-79 specific, 7-{5-[(3-{[(4-tert-butylphenyl)carbamoyl]amino}propyl)(propan-2-yl)amino]-5-deoxy-beta-D-ribofuranosyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine, UNKNOWN ATOM OR ION, ... (4 entities in total)
• 機能のキーワード: histone, methyltransferase, epigenetics, transferase-transferase inhibitor complex, structural genomics, structural genomics consortium, sgc, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Nucleus : Q8TEK3
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 48129.88

構造登録者

Wernimont, A.K.,Tempel, W.,Yu, W.,Scopton, A.,Li, Y.,Nguyen, K.T.,Federation, A.,Marineau, J.,Qi, J.,Vedadi, M.,Bradner, J.E.,Schapira, M.,Arrowsmith, C.H.,Edwards, A.M.,Bountra, C.,Brown, P.J.,Structural Genomics Consortium (SGC) (登録日: 2012-04-19, 公開日: 2012-05-16, 最終更新日: 2024-02-28)

主引用文献

Yu, W.,Chory, E.J.,Wernimont, A.K.,Tempel, W.,Scopton, A.,Federation, A.,Marineau, J.J.,Qi, J.,Barsyte-Lovejoy, D.,Yi, J.,Marcellus, R.,Iacob, R.E.,Engen, J.R.,Griffin, C.,Aman, A.,Wienholds, E.,Li, F.,Pineda, J.,Estiu, G.,Shatseva, T.,Hajian, T.,Al-Awar, R.,Dick, J.E.,Vedadi, M.,Brown, P.J.,Arrowsmith, C.H.,Bradner, J.E.,Schapira, M.
Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors.
Nat Commun, 3:1288-1288, 2012

PubMed Abstract: Selective inhibition of protein methyltransferases is a promising new approach to drug discovery. An attractive strategy towards this goal is the development of compounds that selectively inhibit binding of the cofactor, S-adenosylmethionine, within specific protein methyltransferases. Here we report the three-dimensional structure of the protein methyltransferase DOT1L bound to EPZ004777, the first S-adenosylmethionine-competitive inhibitor of a protein methyltransferase with in vivo efficacy. This structure and those of four new analogues reveal remodelling of the catalytic site. EPZ004777 and a brominated analogue, SGC0946, inhibit DOT1L in vitro and selectively kill mixed lineage leukaemia cells, in which DOT1L is aberrantly localized via interaction with an oncogenic MLL fusion protein. These data provide important new insight into mechanisms of cell-active S-adenosylmethionine-competitive protein methyltransferase inhibitors, and establish a foundation for the further development of drug-like inhibitors of DOT1L for cancer therapy.

PubMed: 23250418
DOI: 10.1038/ncomms2304

実験手法

X-RAY DIFFRACTION (2.57 Å)