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Title | Structural characterization of human tryptophan hydroxylase 2 reveals that L-Phe is superior to L-Trp as the regulatory domain ligand. |
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Journal, issue, pages | Structure, Vol. 31, Issue 6, Page 689-699.e6, Year 2023 |
Publish date | Jun 1, 2023 |
Authors | Ida M Vedel / Andreas Prestel / Zhenwei Zhang / Natalia T Skawinska / Holger Stark / Pernille Harris / Birthe B Kragelund / Günther H J Peters / |
PubMed Abstract | Tryptophan hydroxylase 2 (TPH2) catalyzes the rate-limiting step in serotonin biosynthesis in the brain. Consequently, regulation of TPH2 is relevant for serotonin-related diseases, yet the ...Tryptophan hydroxylase 2 (TPH2) catalyzes the rate-limiting step in serotonin biosynthesis in the brain. Consequently, regulation of TPH2 is relevant for serotonin-related diseases, yet the regulatory mechanism of TPH2 is poorly understood and structural and dynamical insights are missing. We use NMR spectroscopy to determine the structure of a 47 N-terminally truncated variant of the regulatory domain (RD) dimer of human TPH2 in complex with L-Phe, and show that L-Phe is the superior RD ligand compared with the natural substrate, L-Trp. Using cryo-EM, we obtain a low-resolution structure of a similarly truncated variant of the complete tetrameric enzyme with dimerized RDs. The cryo-EM two-dimensional (2D) class averages additionally indicate that the RDs are dynamic in the tetramer and likely exist in a monomer-dimer equilibrium. Our results provide structural information on the RD as an isolated domain and in the TPH2 tetramer, which will facilitate future elucidation of TPH2's regulatory mechanism. |
External links | Structure / PubMed:37119821 |
Methods | EM (single particle) / NMR (solution) |
Resolution | 3.9 - 8.5 Å |
Structure data | EMDB-15853: Tetrameric structure of 47 N-terminally truncated human tryptophan hydroxylase 2 with dimerized regulatory domains EMDB-16223: Cryo-EM structure of the catalytic domain tetramer of N-terminally truncated human tryptophan hydroxylase 2 PDB-7qri: |
Chemicals | ChemComp-PHE: |
Source |
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Keywords | OXIDOREDUCTASE / Tryptophan hydroxylase 2 / serotonin biosynthesis / aromatic amino acid hydroxylase |