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 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.

Structural characterization of human tryptophan hydroxylase 2 reveals L-Phe as the superior regulatory domain ligand relevant for serotonin biosynthesis

“…The dynamic behavior of the RDs is consistent with the monomer-dimer equilibrium of NΔ47-TPH2-RC observed by Tidemand et al 14 . Additionally, our observation is in agreement with a study from Zhu et al, who found that the RDs of an N-terminally tagged full-length TPH2 variant were too dynamic to be observed in their cryo-EM structure of the TPH2 tetramer 34 . Comparing the 2D class averages from the grids without L-Phe (Figure 5D) to the 2D classes with 50 μM L-Phe, did not reveal any significant differences in the overall structure, (Figure 5C-D).…”