中文版 | English
Title

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

Author
Corresponding AuthorWang, Daping; Zhang, Huawei
Joint first authorZhu, Kongfu; Liu, Chao
Publication Years
2022-08-15
DOI
Source Title
EISSN
1663-9812
Volume13
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 angstrom 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.;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 angstrom 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.;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 angstrom 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.;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 angstrom 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.;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 angstrom 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.;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 angstrom 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.

Keywords
URL[Source Record]
Indexed By
Language
English
SUSTech Authorship
First ; 共同第一 ; Corresponding
Funding Project
Science and Technology Innovation Committee of Shenzhen[
WOS Research Area
Pharmacology & Pharmacy ; Pharmacology & Pharmacy ; Pharmacology & Pharmacy ; Pharmacology & Pharmacy ; Pharmacology & Pharmacy ; Pharmacology & Pharmacy
WOS Subject
Pharmacology & Pharmacy ; Pharmacology & Pharmacy ; Pharmacology & Pharmacy ; Pharmacology & Pharmacy ; Pharmacology & Pharmacy ; Pharmacology & Pharmacy
WOS Accession No
WOS:000848053100001
Publisher
Data Source
Web of Science
Citation statistics
Cited Times [WOS]:2
Document TypeJournal Article
Identifierhttp://kc.sustech.edu.cn/handle/2SGJ60CL/395933
DepartmentDepartment of Biomedical Engineering
冷冻电镜中心
Affiliation
1.Southern Univ Sci & Technol, Dept Biomed Engn, Shenzhen, Peoples R China
2.Southern Univ Sci & Technol, Cryo EM Facil Ctr, Shenzhen, Peoples R China
3.Shenzhen Kangning Hosp, Shenzhen Mental Hlth Ctr, Dept Child & Adolescent Psychiat, Shenzhen, Peoples R China
4.Shenzhen Univ, Shenzhen Peoples Hosp 2, Affiliated Hosp 1, Guangdong Prov Res Ctr Artificial Intelligence & D, Shenzhen, Peoples R China
5.Southern Univ Sci & Technol, Guangdong Prov Key Lab Adv Biomat, Shenzhen, Peoples R China
First Author AffilicationDepartment of Biomedical Engineering
Corresponding Author AffilicationDepartment of Biomedical Engineering;  Southern University of Science and Technology
First Author's First AffilicationDepartment of Biomedical Engineering
Recommended Citation
GB/T 7714
Zhu, Kongfu,Liu, Chao,Gao, Yuanzhu,et al. Cryo-EM Structure and Activator Screening of Human Tryptophan Hydroxylase 2[J]. FRONTIERS IN PHARMACOLOGY,2022,13.
APA
Zhu, Kongfu,Liu, Chao,Gao, Yuanzhu,Lu, Jianping,Wang, Daping,&Zhang, Huawei.(2022).Cryo-EM Structure and Activator Screening of Human Tryptophan Hydroxylase 2.FRONTIERS IN PHARMACOLOGY,13.
MLA
Zhu, Kongfu,et al."Cryo-EM Structure and Activator Screening of Human Tryptophan Hydroxylase 2".FRONTIERS IN PHARMACOLOGY 13(2022).
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