8ABX

Crystal structure of IDO1 in complex with Apoxidole-1

8ABX の概要

• エントリーDOI: 10.2210/pdb8abx/pdb
• 分子名称: Indoleamine 2,3-dioxygenase 1, TETRAETHYLENE GLYCOL, TRIETHYLENE GLYCOL, ... (6 entities in total)
• 機能のキーワード: heme-binding protein, natural product, indoleamine 2, 3-dioxygenase 1, oxidoreductase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 47545.67

構造登録者

Dotsch, L.,Ziegler, S.,Waldmann, H.,Gasper, R. (登録日: 2022-07-05, 公開日: 2022-08-24, 最終更新日: 2024-01-31)

主引用文献

Davies, C.,Dotsch, L.,Ciulla, M.G.,Hennes, E.,Yoshida, K.,Gasper, R.,Scheel, R.,Sievers, S.,Strohmann, C.,Kumar, K.,Ziegler, S.,Waldmann, H.
Identification of a Novel Pseudo-Natural Product Type IV IDO1 Inhibitor Chemotype.
Angew.Chem.Int.Ed.Engl., 61:e202209374-e202209374, 2022

PubMed Abstract: Natural product (NP)-inspired design principles provide invaluable guidance for bioactive compound discovery. Pseudo-natural products (PNPs) are de novo combinations of NP fragments to target biologically relevant chemical space not covered by NPs. We describe the design and synthesis of apoxidoles, a novel pseudo-NP class, whereby indole- and tetrahydropyridine fragments are linked in monopodal connectivity not found in nature. Apoxidoles are efficiently accessible by an enantioselective [4+2] annulation reaction. Biological evaluation revealed that apoxidoles define a new potent type IV inhibitor chemotype of indoleamine 2,3-dioxygenase 1 (IDO1), a heme-containing enzyme considered a target for the treatment of neurodegeneration, autoimmunity and cancer. Apoxidoles target apo-IDO1, prevent heme binding and induce unique amino acid positioning as revealed by crystal structure analysis. Novel type IV apo-IDO1 inhibitors are in high demand, and apoxidoles may provide new opportunities for chemical biology and medicinal chemistry research.

PubMed: 35959923
DOI: 10.1002/anie.202209374

実験手法

X-RAY DIFFRACTION (1.65 Å)