7WIY

Cryo-EM structure of human TPH2 tetramer

Summary for 7WIY

• Entry DOI: 10.2210/pdb7wiy/pdb
• EMDB information: 32540
• Descriptor: Tryptophan 5-hydroxylase 2, FE (III) ION, IMIDAZOLE (3 entities in total)
• Functional Keywords: human, tryptophan 5-hydroxylase 2, tetramer, biosynthetic protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 225018.16

Authors

Zhu, K.F.,Liu, C.,Zhang, H.W.,Wang, D.P. (deposition date: 2022-01-05, release date: 2022-10-05, Last modification date: 2024-06-26)

Primary citation

Zhu, K.,Liu, C.,Gao, Y.,Lu, J.,Wang, D.,Zhang, H.
Cryo-EM Structure and Activator Screening of Human Tryptophan Hydroxylase 2.
Front Pharmacol, 13:907437-907437, 2022

PubMed Abstract: Human tryptophan hydroxylase 2 (TPH2) is the rate-limiting enzyme in the synthesis of serotonin. Its dysfunction has been implicated in various psychiatric disorders such as depression, autism, and bipolar disorder. TPH2 is typically decreased in stability and catalytic activity in patients; thus, screening of molecules capable of binding and stabilizing the structure of TPH2 in activated conformation is desired for drug development in mental disorder treatment. Here, we solved the 3.0 Å cryo-EM structure of the TPH2 tetramer. Then, based on the structure, we conducted allosteric site prediction and small-molecule activator screening to the obtained cavity. ZINC000068568685 was successfully selected as the best candidate with highest binding affinity. To better understand the driving forces and binding stability of the complex, we performed molecular dynamics simulation, which indicates that ZINC000068568685 has great potential to stabilize the folding of the TPH2 tetramer to facilitate its activity. The research might shed light on the development of novel drugs targeting TPH2 for the treatment of psychological disorders.

PubMed: 36046836
DOI: 10.3389/fphar.2022.907437

Experimental method

ELECTRON MICROSCOPY (3.09 Å)