6PGR

Cocomplex structure of Deoxyhypusine synthase with inhibitor 6-BROMO-N-(1H-INDOL-4-YL)-1-BENZOTHIOPHENE-2-CARBOXAMIDE

6PGR の概要

• エントリーDOI: 10.2210/pdb6pgr/pdb
• 関連するPDBエントリー: 5V15 5V4J
• 分子名称: Deoxyhypusine synthase, 6-bromo-N-(1H-indol-4-yl)-1-benzothiophene-2-carboxamide (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: 83169.73

構造登録者

Klein, M.G.,Ambrus-Aikelin, G. (登録日: 2019-06-24, 公開日: 2020-04-01, 最終更新日: 2023-10-11)

主引用文献

Tanaka, Y.,Kurasawa, O.,Yokota, A.,Klein, M.G.,Ono, K.,Saito, B.,Matsumoto, S.,Okaniwa, M.,Ambrus-Aikelin, G.,Morishita, D.,Kitazawa, S.,Uchiyama, N.,Ogawa, K.,Kimura, H.,Imamura, S.
Discovery of Novel Allosteric Inhibitors of Deoxyhypusine Synthase.
J.Med.Chem., 63:3215-3226, 2020

PubMed Abstract: Deoxyhypusine synthase (DHPS) utilizes spermidine and NAD as cofactors to incorporate a hypusine modification into the eukaryotic translation initiation factor 5A (eIF5A). Hypusine is essential for eIF5A activation, which, in turn, plays a key role in regulating protein translation of selected mRNA that are associated with the synthesis of oncoproteins, thereby enhancing tumor cell proliferation. Therefore, inhibition of DHPS is a promising therapeutic option for the treatment of cancer. To discover novel lead compounds that target DHPS, we conducted synthetic studies with a hit obtained via high-throughput screening. Optimization of the ring structures of the amide compound () led to bromobenzothiophene () with potent inhibitory activity against DHPS. X-ray crystallographic analysis of complexed with DHPS revealed a dramatic conformational change in DHPS, which suggests the presence of a novel allosteric site. These findings provide the basis for the development of novel therapy distinct from spermidine mimetic inhibitors.

PubMed: 32142284
DOI: 10.1021/acs.jmedchem.9b01979

実験手法

X-RAY DIFFRACTION (1.95 Å)