Title | Cryo-EM Structure and Activator Screening of Human Tryptophan Hydroxylase 2 |
Author | |
Corresponding Author | Wang, Daping; Zhang, Huawei |
Joint first author | Zhu, Kongfu; Liu, Chao |
Publication Years | 2022-08-15
|
DOI | |
Source Title | |
EISSN | 1663-9812
|
Volume | 13 |
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 | Serotonin
Serotonin
Serotonin
Serotonin
Serotonin
Serotonin
Psychological Disorders
Psychological Disorders
Psychological Disorders
Psychological Disorders
Psychological Disorders
Psychological Disorders
TPH2
TPH2
TPH2
TPH2
TPH2
TPH2
Virtual Screening
Virtual Screening
Virtual Screening
Virtual Screening
Virtual Screening
Virtual Screening
MD Simulation
MD Simulation
MD Simulation
MD Simulation
MD Simulation
MD Simulation
|
URL | [Source Record] |
Indexed By | |
Language | English
|
SUSTech Authorship | First
; 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]:1
|
Document Type | Journal Article |
Identifier | http://kc.sustech.edu.cn/handle/2SGJ60CL/395933 |
Department | Department 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 Affilication | Department of Biomedical Engineering |
Corresponding Author Affilication | Department of Biomedical Engineering; Southern University of Science and Technology |
First Author's First Affilication | Department 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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