| 题名 | Cryo-EM structure of ACE2-SIT1 in complex with tiagabine |
| 作者 | |
| 通讯作者 | Yan, Renhong |
| 发表日期 | 2024-09
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| DOI | |
| 发表期刊 | |
| ISSN | 0021-9258
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| EISSN | 1083-351X
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| 卷号 | 300 |
| 摘要 | The pharmacology of amino acid transporters in the SLC6 family is poorly developed compared to that of the neurotransmitter transporters. To identify new inhibitors of the proline transporter SIT1 (SLC6A20), its expression in Xenopus laevis oocytes was optimized. Trafficking of SIT1 was augmented by co-expression of angiotensin-converting enzyme 2 (ACE2) in oocytes but there was no strict requirement for co-expression of ACE2. A pharmacophore-guided screen identified tiagabine as a potent non-competitive inhibitor of SIT1. To understand its binding mode, we determined the cryo-electron microscopy (cryo-EM) structure of ACE2-SIT1 bound with tiagabine. The inhibitor binds close to the orthosteric proline binding site, but due to its size extends into the cytosolic vestibule. This causes the transporter to adopt an inward-open conformation, in which the intracellular gate is blocked. This study provides the first structural insight into inhibition of SIT1 and generates tools for a better understanding of the ACE2-SIT1 complex. These findings may have significance for SARS-CoV-2 binding to its receptor ACE2 in human lung alveolar cells where SIT1 and ACE2 are functionally expressed. © 2024 The Authors |
| 收录类别 | |
| 语种 | 英语
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| 学校署名 | 通讯
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| 资助项目 | The authors thank Stephen Fairweather for help with the preparation of Xenopus laevis oocytes. We thank the Cryo-EM Facility of Southern University of Science and Technology (SUSTech) for providing the facility support. We thank S. Xu, L. Zhang, and P. Li at the Cryo-EM Center of SUSTech for technical support in EM data acquisition. Renhong Yan is an investigator of SUSTech Institute for Biological Electron Microscopy. We thank Zhenyuan Liu for technical support on computing environment. This work was supported by the Natural Science Foundation of Guangdong Province (2024A1515011288 to R. Y.), the Major Talent Recruitment Program of Guangdong Province (2021QNO2Y167 to R. Y.), the Scientific Research and Innovation Project of Medical Discipline (G030410001 to R. Y.) and by NHMRC grant GNT2020757 to S. B. A. B. Z. H. J. K. A. Y. T. Z. and L. D. formal analysis; A. B. Z. H. J. K. A. Y. T. Z. and L. D. investigation; A. B. Z. H. visualization; A. B. Z. H. J. K. A. Y. T. Z. L. D. M. B. R. Y. and S. B. writing-review & editing; M. B. R. Y. and S. B. conceptualization; M. B. R. Y. and S. B. Writing-original draft.The authors thank Stephen Fairweather for help with the preparation of Xenopus laevis oocytes. We thank the Cryo-EM Facility of Southern University of Science and Technology (SUSTech) for providing the facility support. We thank S. Xu, L. Zhang, and P. Li at the Cryo-EM Center of SUSTech for technical support in EM data acquisition. Renhong Yan is an investigator of SUSTech Institute for Biological Electron Microscopy. We thank Zhenyuan Liu for technical support on computing environment. This work was supported by the Natural Science Foundation of Guangdong Province (2024A1515011288 to R.Y.), the Major Talent Recruitment Program of Guangdong Province (2021QNO2Y167 to R.Y.), the Scientific Research and Innovation Project of Medical Discipline (G030410001 to R.Y.) and by NHMRC grant GNT2020757 to S.B..
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| 出版者 | |
| EI入藏号 | 20243717018150
|
| EI主题词 | Binding sites
; Biological membranes
; Electron microscopes
|
| EI分类号 | :103
; :1301.3.1
; :205.1
; Chemistry, General:801.1
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| 来源库 | EV Compendex
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| 引用统计 | |
| 成果类型 | 期刊论文 |
| 条目标识符 | http://sustech.caswiz.com/handle/2SGJ60CL/832823 |
| 专题 | 南方科技大学医学院_生物化学系 南方科技大学 南方科技大学医学院 |
| 作者单位 | 1.Research School of Biology, Australian National University, Canberra, Australia 2.Department of Biochemistry, Key University Laboratory of Metabolism and Health of Guangdong, School of Medicine, Institute for Biological Electron Microscopy, Southern University of Science and Technology, Guangdong, Shenzhen, China 3.Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Cracow, Poland |
| 通讯作者单位 | 生物化学系; 南方科技大学医学院 |
| 推荐引用方式 GB/T 7714 |
Bröer, Angelika,Hu, Ziwei,Kukułowicz, Jędrzej,et al. Cryo-EM structure of ACE2-SIT1 in complex with tiagabine[J]. Journal of Biological Chemistry,2024,300.
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| APA |
Bröer, Angelika.,Hu, Ziwei.,Kukułowicz, Jędrzej.,Yadav, Aditya.,Zhang, Ting.,...&Bröer, Stefan.(2024).Cryo-EM structure of ACE2-SIT1 in complex with tiagabine.Journal of Biological Chemistry,300.
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| MLA |
Bröer, Angelika,et al."Cryo-EM structure of ACE2-SIT1 in complex with tiagabine".Journal of Biological Chemistry 300(2024).
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| 条目包含的文件 | 条目无相关文件。 | |||||
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