4EKI

Crystal Structure of DOT1L in complex with EPZ004777

4EKI の概要

• エントリーDOI: 10.2210/pdb4eki/pdb
• 関連するPDBエントリー: 3QOW 4EK9 4EKG
• 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, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: methyltransferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Nucleus (Probable): Q8TEK3
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 49394.09

構造登録者

Jin, L. (登録日: 2012-04-09, 公開日: 2012-10-17, 最終更新日: 2023-09-13)

主引用文献

Basavapathruni, A.,Jin, L.,Daigle, S.R.,Majer, C.R.,Therkelsen, C.A.,Wigle, T.J.,Kuntz, K.W.,Chesworth, R.,Pollock, R.M.,Scott, M.P.,Moyer, M.P.,Richon, V.M.,Copeland, R.A.,Olhava, E.J.
Conformational adaptation drives potent, selective and durable inhibition of the human protein methyltransferase DOT1L.
Chem.Biol.Drug Des., 80:971-980, 2012

PubMed Abstract: DOT1L is the human protein methyltransferase responsible for catalyzing the methylation of histone H3 on lysine 79 (H3K79). The ectopic activity of DOT1L, associated with the chromosomal translocation that is a universal hallmark of MLL-rearranged leukemia, is a required driver of leukemogenesis in this malignancy. Here, we present studies on the structure-activity relationship of aminonucleoside-based DOT1L inhibitors. Within this series, we find that improvements in target enzyme affinity and selectivity are driven entirely by diminution of the dissociation rate constant for the enzyme-inhibitor complex, leading to long residence times for the binary complex. The biochemical K(i) and residence times measured for these inhibitors correlate well with their effects on intracellular H3K79 methylation and MLL-rearranged leukemic cell killing. Crystallographic studies reveal a conformational adaptation mechanism associated with high-affinity inhibitor binding and prolonged residence time; these studies also suggest that conformational adaptation likewise plays a critical role in natural ligand interactions with the enzyme, hence, facilitating enzyme turnover. These results provide critical insights into the role of conformational adaptation in the enzymatic mechanism of catalysis and in pharmacologic intervention for DOT1L and other members of this enzyme class.

PubMed: 22978415
DOI: 10.1111/cbdd.12050

実験手法

X-RAY DIFFRACTION (2.85 Å)