7ZII
Crystal structure of human tryptophan hydroxylase 1 in complex with inhibitor KM-05-193
Summary for 7ZII
| Entry DOI | 10.2210/pdb7zii/pdb |
| Descriptor | Tryptophan 5-hydroxylase 1, FE (III) ION, 8-(5~{H}-[1,3]dioxolo[4,5-f]benzimidazol-6-ylmethyl)-7-(phenylmethyl)-3-propyl-purine-2,6-dione, ... (5 entities in total) |
| Functional Keywords | tryptophan hydroxylase, serotonin biosynthesis, metal binding protein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 38031.01 |
| Authors | Schuetz, A.,Mallow, K.,Nazare, M.,Specker, E.,Heinemann, U. (deposition date: 2022-04-08, release date: 2022-09-07, Last modification date: 2024-01-31) |
| Primary citation | 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 Cited by 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: 35921615DOI: 10.1021/acs.jmedchem.2c00598 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.62800050605 Å) |
Structure validation
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