4PK5

Crystal structure of the indoleamine 2,3-dioxygenagse 1 (IDO1) complexed with Amg-1

4PK5 の概要

• エントリーDOI: 10.2210/pdb4pk5/pdb
• 関連するPDBエントリー: 4PK6
• 分子名称: Indoleamine 2,3-dioxygenase 1, PROTOPORPHYRIN IX CONTAINING FE, N-(1,3-benzodioxol-5-yl)-2-{[5-(4-methylphenyl)[1,3]thiazolo[2,3-c][1,2,4]triazol-3-yl]sulfanyl}acetamide, ... (4 entities in total)
• 機能のキーワード: indoleamine 2, 3-dioxygenagse 1, induced fit, structure based drug discovery, imidazothiazole, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase 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: 97193.10

構造登録者

Kohno, T.,Tojo, S.,Ishii, T. (登録日: 2014-05-13, 公開日: 2014-09-03, 最終更新日: 2024-11-20)

主引用文献

Tojo, S.,Kohno, T.,Tanaka, T.,Kamioka, S.,Ota, Y.,Ishii, T.,Kamimoto, K.,Asano, S.,Isobe, Y.
Crystal Structures and Structure-Activity Relationships of Imidazothiazole Derivatives as IDO1 Inhibitors.
Acs Med.Chem.Lett., 5:1119-1123, 2014

PubMed Abstract: Indoleamine 2,3-dioxygenase 1 (IDO1) is considered as a promising target for the treatment of several diseases, including neurological disorders and cancer. We report here the crystal structures of two IDO1/IDO1 inhibitor complexes, one of which shows that Amg-1 is directly bound to the heme iron of IDO1 with a clear induced fit. We also describe the identification and preliminary optimization of imidazothiazole derivatives as novel IDO1 inhibitors. Using our crystal structure information and structure-activity relationships (SAR) at the pocket-B of IDO1, we found a series of urea derivatives as potent IDO1 inhibitors and revealed that generation of an induced fit and the resulting interaction with Phe226 and Arg231 are essential for potent IDO1 inhibitory activity. The results of this study are very valuable for understanding the mechanism of IDO1 activation, which is very important for structure-based drug design (SBDD) to discover potent IDO1 inhibitors.

PubMed: 25313323
DOI: 10.1021/ml500247w

実験手法

X-RAY DIFFRACTION (2.79 Å)