6WL6

Cocomplex structure of Deoxyhypusine synthase with inhibitor 6-[(2R)-1-AMINO-4-METHYLPENTAN-2-YL]-3-(PYRIDIN-3-YL)-4H,5H,6H,7H-THIENO[2,3-C]PYRIDIN-7-ONE

6WL6 の概要

• エントリーDOI: 10.2210/pdb6wl6/pdb
• 関連するPDBエントリー: 5V15 5V2E 5V4J
• 分子名称: Deoxyhypusine synthase, 6-[(2R)-1-amino-4-methylpentan-2-yl]-3-(pyridin-3-yl)-5,6-dihydrothieno[2,3-c]pyridin-7(4H)-one (3 entities in total)
• 機能のキーワード: deoxyhypusine, inhibitor, transferase, transferase-inhibitor complex, transferase/inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 83086.15

構造登録者

Klein, M.G.,Ambrus-Aikelin, G. (登録日: 2020-04-18, 公開日: 2020-08-19, 最終更新日: 2023-10-18)

主引用文献

Tanaka, Y.,Kurasawa, O.,Yokota, A.,Klein, M.G.,Saito, B.,Matsumoto, S.,Okaniwa, M.,Ambrus-Aikelin, G.,Uchiyama, N.,Morishita, D.,Kimura, H.,Imamura, S.
New Series of Potent Allosteric Inhibitors of Deoxyhypusine Synthase.
Acs Med.Chem.Lett., 11:1645-1652, 2020

PubMed Abstract: Deoxyhypusine synthase (DHPS) is the primary enzyme responsible for the hypusine modification and, thereby, activation of the eukaryotic translation initiation factor 5A (eIF5A), which is key in regulating the protein translation processes associated with tumor proliferation. Although DHPS inhibitors could be a promising therapeutic option for treating cancer, only a few studies reported druglike compounds with this inhibition property. Thus, in this work, we designed and synthesized a new chemical series possessing fused ring scaffolds designed from high-throughput screening hit compounds, discovering a 5,6-dihydrothieno[2,3-]pyridine derivative () with potent inhibitory activity; furthermore, the X-ray crystallographic analysis of the DHPS complex with demonstrated a distinct allosteric binding mode compared to a previously reported inhibitor. These findings could be significantly useful in the functional analysis of conformational changes in DHPS as well as the structure-based design of allosteric inhibitors.

PubMed: 34345355
DOI: 10.1021/acsmedchemlett.0c00331

実験手法

X-RAY DIFFRACTION (2.12 Å)