7ZIJ

Crystal structure of human tryptophan hydroxylase 1 in complex with inhibitor KM-05-080

7ZIJ の概要

• エントリーDOI: 10.2210/pdb7zij/pdb
• 分子名称: Tryptophan 5-hydroxylase 1, 8-(1~{H}-benzimidazol-2-ylmethyl)-3-cyclopropyl-7-(phenylmethyl)purine-2,6-dione, FE (III) ION, ... (4 entities in total)
• 機能のキーワード: tryptophan hydroxylase, serotonin biosynthesis, metal binding protein
• 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: 37892.89

構造登録者

Schuetz, A.,Mallow, K.,Nazare, M.,Specker, E.,Heinemann, U. (登録日: 2022-04-08, 公開日: 2022-09-07, 最終更新日: 2024-01-31)

主引用文献

Specker, E.,Matthes, S.,Wesolowski, R.,Schutz, A.,Grohmann, M.,Alenina, N.,Pleimes, D.,Mallow, K.,Neuenschwander, M.,Gogolin, A.,Weise, M.,Pfeifer, J.,Ziebart, N.,Heinemann, U.,von Kries, J.P.,Nazare, M.,Bader, M.
Structure-Based Design of Xanthine-Benzimidazole Derivatives as Novel and Potent Tryptophan Hydroxylase Inhibitors.
J.Med.Chem., 65:11126-11149, 2022

PubMed Abstract: Tryptophan hydroxylases catalyze the first and rate-limiting step in the synthesis of serotonin. Serotonin is a key neurotransmitter in the central nervous system and, in the periphery, functions as a local hormone with multiple physiological functions. Studies in genetically altered mouse models have shown that dysregulation of peripheral serotonin levels leads to metabolic, inflammatory, and fibrotic diseases. Overproduction of serotonin by tumor cells causes severe symptoms typical for the carcinoid syndrome, and tryptophan hydroxylase inhibitors are already in clinical use for patients suffering from this disease. Here, we describe a novel class of potent tryptophan hydroxylase inhibitors, characterized by spanning all active binding sites important for catalysis, specifically those of the cosubstrate pterin, the substrate tryptophan as well as directly chelating the catalytic iron ion. The inhibitors were designed to efficiently reduce serotonin in the periphery while not passing the blood-brain barrier, thus preserving serotonin levels in the brain.

PubMed: 35921615
DOI: 10.1021/acs.jmedchem.2c00598

実験手法

X-RAY DIFFRACTION (1.94678362883 Å)