Cryo-EM Structure and Activator Screening of Human Tryptophan Hydroxylase 2
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, s...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2022-08-01
|
| Series: | Frontiers in Pharmacology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.907437/full |
| _version_ | 1811321313466253312 |
|---|---|
| author | Kongfu Zhu Chao Liu Yuanzhu Gao Jianping Lu Daping Wang Daping Wang Huawei Zhang Huawei Zhang |
| author_facet | Kongfu Zhu Chao Liu Yuanzhu Gao Jianping Lu Daping Wang Daping Wang Huawei Zhang Huawei Zhang |
| author_sort | Kongfu Zhu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-13T13:15:22Z |
| format | Article |
| id | doaj.art-97cbf41bb00e4fce8ca28ac46c8cec6d |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-13T13:15:22Z |
| publishDate | 2022-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-97cbf41bb00e4fce8ca28ac46c8cec6d2022-12-22T02:45:29ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-08-011310.3389/fphar.2022.907437907437Cryo-EM Structure and Activator Screening of Human Tryptophan Hydroxylase 2Kongfu Zhu0Chao Liu1Yuanzhu Gao2Jianping Lu3Daping Wang4Daping Wang5Huawei Zhang6Huawei Zhang7Department of Biomedical Engineering, Southern University of Science and Technology, Shenzhen, ChinaDepartment of Biomedical Engineering, Southern University of Science and Technology, Shenzhen, ChinaCryo-EM Facility Center, Southern University of Science and Technology, Shenzhen, ChinaDepartment of Child and Adolescent Psychiatry, Shenzhen Kangning Hospital, Shenzhen Mental Health Center, Shenzhen, ChinaDepartment of Biomedical Engineering, Southern University of Science and Technology, Shenzhen, ChinaDepartment of Orthopedics, Shenzhen Intelligent Orthopaedics and Biomedical Innovation Platform, Guangdong Provincial Research Center for Artificial Intelligence and Digital Orthopedic Technology, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, ChinaDepartment of Biomedical Engineering, Southern University of Science and Technology, Shenzhen, ChinaGuangdong Provincial Key Laboratory of Advanced Biomaterials, Southern University of Science and Technology, Shenzhen, ChinaHuman 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.https://www.frontiersin.org/articles/10.3389/fphar.2022.907437/fullserotoninpsychological disordersTPH2virtual screeningMD simulation |
| spellingShingle | Kongfu Zhu Chao Liu Yuanzhu Gao Jianping Lu Daping Wang Daping Wang Huawei Zhang Huawei Zhang Cryo-EM Structure and Activator Screening of Human Tryptophan Hydroxylase 2 Frontiers in Pharmacology serotonin psychological disorders TPH2 virtual screening MD simulation |
| title | Cryo-EM Structure and Activator Screening of Human Tryptophan Hydroxylase 2 |
| title_full | Cryo-EM Structure and Activator Screening of Human Tryptophan Hydroxylase 2 |
| title_fullStr | Cryo-EM Structure and Activator Screening of Human Tryptophan Hydroxylase 2 |
| title_full_unstemmed | Cryo-EM Structure and Activator Screening of Human Tryptophan Hydroxylase 2 |
| title_short | Cryo-EM Structure and Activator Screening of Human Tryptophan Hydroxylase 2 |
| title_sort | cryo em structure and activator screening of human tryptophan hydroxylase 2 |
| topic | serotonin psychological disorders TPH2 virtual screening MD simulation |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.907437/full |
| work_keys_str_mv | AT kongfuzhu cryoemstructureandactivatorscreeningofhumantryptophanhydroxylase2 AT chaoliu cryoemstructureandactivatorscreeningofhumantryptophanhydroxylase2 AT yuanzhugao cryoemstructureandactivatorscreeningofhumantryptophanhydroxylase2 AT jianpinglu cryoemstructureandactivatorscreeningofhumantryptophanhydroxylase2 AT dapingwang cryoemstructureandactivatorscreeningofhumantryptophanhydroxylase2 AT dapingwang cryoemstructureandactivatorscreeningofhumantryptophanhydroxylase2 AT huaweizhang cryoemstructureandactivatorscreeningofhumantryptophanhydroxylase2 AT huaweizhang cryoemstructureandactivatorscreeningofhumantryptophanhydroxylase2 |