7QRI

Regulatory domain dimer of tryptophan hydroxylase 2 in complex with L-Phe

Summary for 7QRI

• Entry DOI: 10.2210/pdb7qri/pdb
• NMR Information: BMRB: 34698
• Descriptor: Tryptophan 5-hydroxylase 2, PHENYLALANINE (2 entities in total)
• Functional Keywords: tryptophan hydroxylase 2, serotonin biosynthesis, aromatic amino acid hydroxylase, oxidoreductase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 22898.10

Authors

Vedel, I.M.,Prestel, A.,Harris, P.,Peters, G.H.J.,Kragelund, B.B. (deposition date: 2022-01-11, release date: 2023-05-03, Last modification date: 2024-06-19)

Primary citation

Vedel, I.M.,Prestel, A.,Zhang, Z.,Skawinska, N.T.,Stark, H.,Harris, P.,Kragelund, B.B.,Peters, G.H.J.
Structural characterization of human tryptophan hydroxylase 2 reveals that L-Phe is superior to L-Trp as the regulatory domain ligand.
Structure, 31:689-, 2023

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 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.

PubMed: 37119821
DOI: 10.1016/j.str.2023.04.004

Experimental method

SOLUTION NMR