Cryo-EM Structure and Activator Screening of Human Tryptophan Hydroxylase 2.

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 force

SUBMITTER: Zhu K 

PROVIDER: S-EPMC9420949 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature