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• W4367311923 endingPage "699.e6" @default.
• W4367311923 startingPage "689" @default.
• W4367311923 abstract "•The structure of the regulatory domain dimer of tryptophan hydroxylase 2 was determined •Two L-Phe molecules are bound at the dimer interface in the regulatory domain dimer •L-Phe binds more strongly than L-Trp to the regulatory domain dimer •A low-resolution structure of tetrameric TPH2 was determined with cryo-EM 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. 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." @default.
• W4367311923 created "2023-04-29" @default.
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• W4367311923 date "2023-06-01" @default.
• W4367311923 modified "2023-09-27" @default.
• W4367311923 title "Structural characterization of human tryptophan hydroxylase 2 reveals that L-Phe is superior to L-Trp as the regulatory domain ligand" @default.
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• W4367311923 doi "https://doi.org/10.1016/j.str.2023.04.004" @default.
• W4367311923 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/37119821" @default.
• W4367311923 hasPublicationYear "2023" @default.
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