Principal investigator
Name:
Fei XuProfessor , PhD, Professor
Position:
Affiliation:
School of Life Science and Technology/ iHuman Institute
Honor:
Education Background:
- 2006/07-2011/06, Biology The Scripps Research Institute (TSRI), La Jolla, California, USA, Ph.D.
- 2002/09-2006/07, Biological Sciences University of Science and Technology of China (USTC), Hefei, China, B.S.
Working Experience:
- 2023/11-Present, School of Life Science and Technology, ShanghaiTech Universtiy, Professor (TENURED）
- 2019/12-2023/11, School of Life Science and Technology, ShanghaiTech Universtiy, Associate Professor (TENURED)
- 2014/08-2019/12, School of Life Science and Technology, ShanghaiTech University, Assistant Professor (TENURE-TRACK), PI
- 2013/09-Present, iHuman Institute, ShanghaiTech University, Research Associate Professor,Principle Investigator
- 2012/09-2013/09, RuiYi Inc., La Jolla, CA, USA, Scientific Consultant
- 2011/08-2012/09, RuiYi Biopharmaceutics Technology Co., Ltd., Shanghai, China, Founder and Director, R&D
Group Introduction
Research Area:
Structural Biology
Research Interests:
Our research focuses on employing a combination of cutting-edge membrane protein structural biology and cell biology methods. Through broad interdisciplinary collaboration, we delve into the study of a class of G protein-coupled receptor (GPCR) targets closely associated with human diseases, yet whose structures and mechanisms remain elusive. These targets primarily include orphan receptors, with unknown endogenous ligands, a class of non-canonical GPCR, Frizzled receptors, regulating the Wnt signaling pathway, as well as receptors and ion channels closely related to mental disorder. Our research encompasses various aspects of target protein, including three-dimensional structure and oligomeric forms, ligand recognition and modulating mechanisms, receptor activation or self-activation mechanisms, and the structure and function of signaling transduction complexes. By gaining in-depth insights into the structure and function of these proteins, we aim to provide guidance for the screening of small molecules and antibodies, driving the discovery and development of relevant drugs.
Research Achievement
Our research group employs cutting-edge G protein-coupled receptor (GPCR) technologies to address pivotal biological questions and advance drug development and applications. We have reported the structure of the TAAR1 receptor, a target for addictive drugs like methamphetamine, elucidating the ligand recognition and structural pharmacological mechanisms of this crucial target in mental disorders. This paper was published as AAP (accelerated article preview) on “Nature in Nov 7, 2023. We have also analyzed the three-dimensional structures of distinct functional states of the first human orphan receptor GPR52, proposing a unique self-activation mechanism with high basal activity specific to orphan receptors. The relevant papers and a series of subsequent works were published in Nature (2022), in Nature Communications (2023) and Cell Discovery (2023) among other journals. The first protein structure in the Frizzled receptor family revealed unique structural features and the research potential of these proteins as potential cancer targets. Related work and subsequent research were published in Nature (2018), Cell Research (2021), and the recently accepted Cell Discovery. We have also elucidated the high-resolution structure of the human apelin receptor binding to endogenous peptide ligands, unraveling the mystery of class-A GPCR dimerization. The relevant work was published in Nature Structural & Molecular Biology in 2022 and Structure in 2017. Additionally, our research around GPCR and ion channel targets related to mental disorders, cancers, etc., has led to a series of original scientific discoveries, with outcomes published in academic journals such as Neuron, Protein & Cell, J Med Chem and others.
Representative Publications (*First Author, # Corresponding Author)
- 1. Heng Liu*, You Zheng*, Yue Wang*, Yumeng Wang*, Xinheng He, Peiyu Xu, Sijie Huang, Qingning Yuan, Xinyue Zhang, Ling Wang, Kexin Jiang, Hong Chen, Zhen Li, Wenbin Liu##, Sheng Wang##, H. Eric Xu##, Fei Xu##.Recognition of methamphetamine and other amines by trace amine receptor TAAR1.Nature. Nov 2023.
- 2. Li, Cuixia*; Wu, Yiran; Wang, Wenli; Xu, Lu; Zhou, Yan; Yue, Yang; Wu, Tingting; Yang, Meifang; Qiu, Yanli; Huang, Minhao; Zhou, Fangfang; Zhou, Yiqing; Hao, Piliang; Lin, Zhixiong; Wang, Ming-Wei; Zhao, Suwen#; Yang, Dehua#; Xu, Fei#; Tao, Houchao#; .Structure-Based Ligand Discovery Targeting the Transmembrane Domain of Frizzled Receptor FZD7.JOURNAL OF MEDICINAL CHEMISTRY. 05 Sep 2023.
- 3. Lin, Xi*; Jiang, Shan*; Wu, Yiran; Wei, Xiaohu; Han, Gye-Won; Wu, Lijie; Liu, Junlin; Chen, Bo; Zhang, Zhibin; Zhao, Suwen; Cherezov, Vadim; Xu, Fei#.The activation mechanism and antibody binding mode for orphan GPR20.CELL DISCOVERY;. 01 Dec 2023. 9(1).
- 4. Lin Xi*, Chen B*, Wu Y*, Han Y, Qi A, Wang J, Yang Z, Wei X, Zhao T, Wu L, Xie X, Sun J, Zheng J#, Zhao S#, Xu F#.Cryo-EM structures of orphan GPR21 signaling complexes.Nature Communications. Jan 2023.
- 5. Yue, Yang*; Liu, Lier*; Wu, Li-Jie*; Wu, Yiran; Wang, Ling; Li, Fei; Liu, Junlin; Han, Gye-Won; Chen, Bo; Lin, Xi; Brouillette, Rebecca L.; Breault, Emile; Longpre, Jean-Michel; Shi, Songting; Lei, Hui; Sarret, Philippe; Stevens, Raymond C.; Hanson, Michael A.; Xu, Fei#.Structural insight into apelin receptor-G protein stoichiometry.NATURE STRUCTURAL & MOLECULAR BIOLOGY. Jul 2022. 29(7).
- 6. Chen Yuxiang*, Chen B*, Wu T*, Zhou F, Xu F#.Cryo-EM structure of human κ-opioid receptor-Gi complex bound to an endogenous agonist dynorphin A.Protein & Cell. Aug 2022.
- 7. Zheng, You*; Liu, Heng; Chen, Yuxin; Dong, Shaowei; Wang, Fang; Wang, Shengyi; Li, Geng-Lin; Shu, Yilai#; Xu, Fei#.Structural insights into the lipid and ligand regulation of a human neuronal KCNQ channel.NEURON. 19 Jan 2022. 110(2).
- 8. Xu, Lu*; Chen, Bo; Schihada, Hannes; Wright, Shane C.; Turku, Ainoleena; Wu, Yiran; Han, Gye-Won; Kowalski-Jahn, Maria; Kozielewicz, Pawel; Bowin, Carl-Fredrik; Zhang, Xianjun; Li, Chao; Bouvier, Michel; Schulte, Gunnar#; Xu, Fei#.Cryo-EM structure of constitutively active human Frizzled 7 in complex with heterotrimeric G(s).CELL RESEARCH. Dec 2021.
- 9. Lin, Xi*; Li, Mingyue*; Wang, Niandong*; Wu, Yiran*; Luo, Zhipu; Guo, Shimeng; Han, Gye-Won; Li, Shaobai; Yue, Yang; Wei, Xiaohu; Xie, Xin; Chen, Yong; Zhao, Suwen; Wu, Jian#; Lei, Ming#; Xu, Fei#.Structural basis of ligand recognition and self-activation of orphan GPR52.NATURE. 19 Feb 2020.
- 10. Yang, Shifan*; Wu, Yiran; Xu, Ting-Hai; de Waal, Parker W.; He, Yuanzheng; Pu, Mengchen; Chen, Yuxiang; DeBruine, Zachary J.; Zhang, Bingjie; Zaidi, Saheem A.; Popov, Petr; Guo, Yu; Han, Gye Won; Lu, Yang; Suino-Powell, Kelly; Dong, Shaowei; Harikumar, Kaleeckal G.; Miller, Laurence J.; Katritch, Vsevolod; Xu, H. Eric; Shui, Wenqing; Stevens, Raymond C.; Melcher, Karsten; Zhao, Suwen; Xu, Fei#.Crystal structure of the Frizzled 4 receptor in a ligand-free state.NATURE. 2018. 560(7720):666-670.
- 11. Zhang, Xianjun*; Zhao, Fei; Wu, Yiran; Yang, Jun; Han, Gye Won; Zhao, Suwen; Ishchenko, Andrii; Ye, Lintao; Lin, Xi; Ding, Kang; Dharmarajan, Venkatasubramanian; Griffin, Patrick R.; Gati, Cornelius; Nelson, Garrett; Hunter, Mark S.; Hanson, Michael A.; Cherezov, Vadim; Stevens, Raymond C.; Tan, Wenfu#; Tao, Houchao#; Xu, Fei#.Crystal structure of a multi-domain human smoothened receptor in complex with a super stabilizing ligand.NATURE COMMUNICATIONS. 17 May 2017. 8(1).
- 12. Zhang, Xianjun*; Dong, Shaowei; Xu, Fei#.Structural and Druggability Landscape of Frizzled G Protein-Coupled Receptors.TRENDS IN BIOCHEMICAL SCIENCES. Dec 2018. 43(12):1033-1046.
- 13. Xu, Fei*; Wu, Huixian; Katritch, Vsevolod; Han, Gye Won; Jacobson, Kenneth A.; Gao, Zhan-Guo; Cherezov, Vadim; Stevens, Raymond C.#.Structure of an Agonist-Bound Human A(2A) Adenosine Receptor.SCIENCE. 2011. 332(6027):322-327.
- 14. Zhang, Xianjun*; Stevens, Raymond C.; Xu, Fei#.The importance of ligands for G protein-coupled receptor stability.TRENDS IN BIOCHEMICAL SCIENCES. Feb 2015. 40(2):79-87.
- 15. Ma, Yingli*; Yue, Yang; Ma, Yanbin; Zhang, Qing; Zhou, Qingtong; Song, Yunpeng; Shen, Yuqing; Li, Xun; Ma, Xiaochuan; Li, Chao; Hanson, Michael A.; Han, Gye Won; Sickmier, E. Allen; Swaminath, Gayathri; Zhao, Suwen; Stevens, Raymond C.; Hu, Liaoyuan A.; Zhong, Wenge; Zhang, Mingqiang; Xu, Fei#.Structural Basis for Apelin Control of the Human Apelin Receptor.STRUCTURE. 06 Jun 2017. 25(6):858-+.
- 16. Xu, Fei*; Liu, Wei; Hanson, Michael A.; Stevens, Raymond C.; Cherezov, Vadim#.Development of an Automated High Throughput LCP-FRAP Assay to Guide Membrane Protein Crystallization in Lipid Mesophases.CRYSTAL GROWTH & DESIGN. 2011. 11(4):1193-1201.
- 17. Xu, Fei*; Stevens, Raymond C.#.Trapping Small Caffeine in a Large GPCR Pocket.STRUCTURE. 2011. 19(9):1204-1207.
- 18. Liu, Wei*; Chun, Eugene; Thompson, Aaron A.; Chubukov, Pavel; Xu, Fei; Katritch, Vsevolod; Han, Gye Won; Roth, Christopher B.; Heitman, Laura H.; IJzerman, Adriaan P.; Cherezov, Vadim#; Stevens, Raymond C.#.Structural Basis for Allosteric Regulation of GPCRs by Sodium Ions.SCIENCE. 2012. 337(6091):232-236.
- 19. Chun, Eugene*; Thompson, Aaron A.; Liu, Wei; Roth, Christopher B.; Griffith, Mark T.; Katritch, Vsevolod; Kunken, Joshua; Xu, Fei; Cherezov, Vadim; Hanson, Michael A.#; Stevens, Raymond C.#.Fusion Partner Toolchest for the Stabilization and Crystallization of G Protein-Coupled Receptors.STRUCTURE. 2012. 20(6):967-976.
- 20. Tosh, Dilip K.*; Phan, Khai; Gao, Zhan-Guo; Gakh, Andrei A.; Xu, Fei; Deflorian, Francesca; Abagyan, Ruben; Stevens, Raymond C.; Jacobson, Kenneth A.#; Katritch, Vsevolod#.Optimization of Adenosine 5 '-Carboxamide Derivatives as Adenosine Receptor Agonists Using Structure-Based Ligand Design and Fragment Screening.JOURNAL OF MEDICINAL CHEMISTRY. 2012. 55(9):4297-4308.
- 21. Deflorian, Francesca*; Kumar, T. Santhosh; Phan, Khai; Gao, Zhan-Guo; Xu, Fei; Wu, Huixian; Katritch, Vsevolod; Stevens, Raymond C.; Jacobson, Kenneth A.#.Evaluation of Molecular Modeling of Agonist Binding in Light of the Crystallographic Structure of an Agonist-Bound A(2A) Adenosine Receptor.JOURNAL OF MEDICINAL CHEMISTRY. 2012. 55(1):538-552.
- 22. Xue, Dongxiang*; Ye, Lintao; Zheng, Jun; Wu, Yiran; Zhang, Xianjun; Xu, Yueming; Li, Tao; Stevens, Raymond C.; Xu, Fei; Zhuang, Min; Zhao, Suwen; Zhao, Fei#; Tao, Houchao#.The structure-based traceless specific fluorescence labeling of the smoothened receptor.ORGANIC & BIOMOLECULAR CHEMISTRY. 07 Jul 2019. 17(25):6136-6142.
- 23. Ye, Lintao*; Ding, Kang; Zhao, Fei; Liu, Xiaoyan; Wu, Yiran; Liu, Yang; Xue, Dongxiang; Zhou, Fang; Zhang, Xianjun; Stevens, Raymond C.; Xu, Fei; Zhao, Suwen#; Tao, Houchao#.A structurally guided dissection-then-evolution strategy for ligand optimization of smoothened receptor.MEDCHEMCOMM. Jun 2017. 8(6):1332-1336.
- 24. Zhao, Huan*; Tian, Xueying; He, Lingjuan; Li, Yan; Pu, Wenjuan; Liu, Qiaozhen; Tang, Juan; Wu, Jiaying; Cheng, Xin; Liu, Yang; Zhou, Qingtong; Tan, Zhen; Bai, Fan; Xu, Fei; Smart, Nicola; Zhou, Bin#.Apj(+) Vessels Drive Tumor Growth and Represent a Tractable Therapeutic Target.CELL REPORTS. 30 Oct 2018. 25(5):1241-+.
- 25. Zhou, F.*; Ding, K.; Zhou, Y.; Liu, Y.; Liu, X.; Zhao, F.; Wu, Y.; Zhang, X.; Xu, F.; Zhao, S.; Tao, H..Determination of an underneath binding in the transmembrane domain of smoothened receptor.JOURNAL OF BIOENERGETICS AND BIOMEMBRANES. Dec 2018. 50(6):510-510.
- 26. Lin, X.*; Xu, F..Toward the first orphan GPCR structure.JOURNAL OF BIOENERGETICS AND BIOMEMBRANES. Dec 2018. 50(6):559-559.
- 27. Zhou, Fang*; Ding, Kang; Zhou, Yiqing; Liu, Yang; Liu, Xiaoyan; Zhao, Fei; Wu, Yiran; Zhang, Xianjun; Tan, Qiwen; Xu, Fei; Tan, Wenfu; Xiao, Youli#; Zhao, Suwen#; Tao, Houchao#.Colocalization Strategy Unveils an Underside Binding Site in the Transmembrane Domain of Smoothened Receptor.JOURNAL OF MEDICINAL CHEMISTRY. 14 Nov 2019. 62(21):9983-9989.
- 28. Lin, Xi*; Chen, Bo; Wu, Yiran; Han, Yingqi; Qi, Ao; Wang, Junyan; Yang, Zhao; Wei, Xiaohu; Zhao, Tingting; Wu, Lijie; Xie, Xin; Sun, Jinpeng; Zheng, Jie#; Zhao, Suwen#; Xu, Fei#.Cryo-EM structures of orphan GPR21 signaling complexes.NATURE COMMUNICATIONS;. 01 Dec 2023. 14(1).
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