9HB7

Crystal structure of human tryptophan hydroxylase 2 in complex with inhibitor AG-01-128

Summary for 9HB7

• Entry DOI: 10.2210/pdb9hb7/pdb
• Descriptor: Tryptophan 5-hydroxylase 2, FE (III) ION, 8-(1~{H}-benzimidazol-2-ylmethyl)-3-ethyl-7-(phenylmethyl)purine-2,6-dione, ... (4 entities in total)
• Functional Keywords: tryptophan hydroxylase 2, serotonin biosynthesis, metal binding protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 86423.50

Authors

Schuetz, A.,Gogolin, A.,Pfeifer, J.,Mallow, K.,Nazare, M.,Specker, E.,Heinemann, U. (deposition date: 2024-11-05, release date: 2025-07-16)

Primary citation

Wesolowski, R.,Schutz, A.,Lisurek, M.,Nazare, M.,Heinemann, U.,Pleimes, D.,Bader, M.,Specker, E.
Selectivity and Safety Characterization of a Xanthine-Imidazothiazole Lead Structure: a Novel Tryptophan Hydroxylase Inhibitor of Peripheral Serotonin Synthesis.
Acs Pharmacol Transl Sci, 8:1678-1693, 2025

PubMed Abstract: Serotonin (5-HT), a crucial neurotransmitter and peripheral mediator, regulates various physiological processes and is synthesized by tryptophan hydroxylase 1 (TPH1), the rate-limiting enzyme responsible for its production. 5-HT overproduction is implicated in multiple diseases, making TPH1 a promising therapeutic target. However, selectivity remains a challenge due to the structural similarity of TPH1 with other members of the aromatic amino acid hydroxylase (AAAH) family, including TPH2, phenylalanine hydroxylase (PAH), and tyrosine hydroxylase (TH). This study aimed to evaluate the selectivity and inhibitory potential of TPT-004, a novel TPH inhibitor, compared with Telotristat (LP778902) and its prodrug (LX1606). We developed high-throughput fluorescence assays to evaluate the inhibitory effects of the test compounds on TPH1, TPH2, PAH, and TH enzymes. TPT-004 demonstrated high selectivity for TPHs compared to LP778902 and LX1606. Structural analysis based on a detailed sequence alignment within the AAAH enzyme family, combined with cocrystal structures of TPH1 and TPH2 bound to different generations of inhibitors, enhances our understanding of the molecular basis of inhibitor binding and provides a framework for explaining TPT-004's selectivity for TPHs. Selectivity profiling against 97 targets confirmed that TPT-004 showed minimal off-target interactions, underscoring its specificity. A dose-range finding (DRF) study in rats assessed the safety profile of TPT-004, showing no adverse effects on survival and body weight at doses up to 400 mg/kg/day. Hematology parameters remained normal, with only minor liver changes observed. These results highlight TPT-004's potential as a selective and safe TPH inhibitor, offering a promising therapeutic option for serotonin-related disorders.

PubMed: 40534674
DOI: 10.1021/acsptsci.5c00043

Experimental method

X-RAY DIFFRACTION (2.95518755358 Å)