Cellular signal transduction by G-protein coupled receptors

Prof. Fei Xu

ShanghaiTech University

DATE: 28th August 2019
TIME: 17:30 – 18:30 pm
LOCATION: Rigoni Stern Institute, Asiago

G-protein coupled receptor (GPCR) superfamily constitutes the largest protein family in the human genome with >800 members which are responsible for over 80% signal transduction across the cell membranes. The signals can be as simple as light, ions, hormones to as diverse as proteins, lipids, olfactory molecules. The fact that we can see, taste, smell, and feel hungry, most of the time, is because of GPCRs and the signal transduction that they mediate.  As such, malfunction of GPCR signal transduction will lead to numerous human diseases, including cancer, inflammation, cardiovascular and metabolic disorders, and a variety of neurological disorders such as Parkinson’s diseases, depression and so on. GPCRs are thus targets for over one-third marketed drugs that we now use for treating diseases.  Fundamental research of their 3D structure and receptor function are extremely important for understanding the molecular mechanism of signal transduction. Such an understanding paves the way toward structure-based rational drug design, complementary to the traditional pharmacology and mechanism-based drug screening campaign. GPCR structural studies are growing fast recently owing to the rapid development of GPCR structure-function study pipelines and the advancement of cryo-EM technology. In this lecture, I will guide the students to go through the accumulated knowledge that we have gained for GPCRs and to show that these knowledge will lay the foundation for future therapeutic discoveries.


Sep 2013- present Sep 2014- present Sep 2012- Sep 2013 Aug 2011- Sep 2012 July 2006- June 2011 Sep 2002- July 2006 China

Curriculum Vitae

Fei Xu, Ph.D.

xufei@shanghaitech.edu.cn http://xulab.shanghaitech.edu.cn

Research Associate Professor, iHuman Institute, ShanghaiTech University
Assistant Professor, Tenure-Track, School of Life Science, ShanghaiTech University Scientific Consultant, RuiYi Inc., La Jolla, CA, USA and Shanghai, China
Founder and Director of R&D, RuiYi Inc., La Jolla, CA, USA and Shanghai, China
Ph.D. in Biology, The Scripps Research Institute (TSRI), La Jolla, California, USA
B.S. in Biological Sciences, University of Science and Technology of China (USTC), Hefei,


Sep 2013- present iHuman Institute, ShanghaiTech University, Shanghai, ChinaAssistant Professor

  •   My research interests at ShanghaiTech University center on deciphering the signaling pathways of G- protein coupled receptor (GPCR) in human cells, with an emphasis on GPCR signaling in developmental biology.
  •   My lab takes advantage of recent advances in GPCR structure and function research, including technologies such as LCP aided micro-crystallography, single particle cryo-EM reconstruction, and tool ligand screening for molecular probing. This is in combination with other biophysical approaches to explore the critical involvement of GPCRs in embryogenesis and tissue homeostasis regulation. We will examine the relevance and means of intervention of dysregulated GPCR signaling to numerous human diseases in order to make new therapeutics.
  •   As a principle investigator, I have published three research articles and two review articles on high-impact journals, including Nature, Nature Communications and Structure (Cell press).Aug 2011- Sep 2013 RuiYi Inc (now Bird Rock Bio), La Jolla, CA, USA and Shanghai, ChinaCo-Founder, Director of R&D, and Scientific Consultant
  •   I co-founded this biotech startup company with Prof. Ray Stevens in Shanghai, China. We were one of the first biotech startups in China born from a US-China network.
  •   We built our proprietary GPCR antigen generation pipeline, directed GPCR target selection, worked with Shanghai contract research organizations (CROs) to conduct the antigen preparation and assay development, and reached all our milestones.
  •   This work led to the development of a first-in-class antibody called Namacizumab, a negative allosteric modulator of the CB1 GPCR. It is currently in clinical trials for fibrotic and metabolic diseases.RESEARCH EXPERIENCEMay 2009-June 2011 Dept. of Molecular Biology, TSRI
    Research as Graduate Student with Advisor Raymond Stevens

 In less than two years in Prof. Stevens’ lab, I determined the complex structure of the A2A adenosine receptor bound to a full agonist, showing the structural basis for GPCR activation and signal transduction. This study was published in Science in April 2011, soon rated as Faculty of 1000 Biology’s “Exceptional”

Curriculum Vitae and “Must Read” paper and Highlighted in Nature magazine, NIGMS, Science Daily, and other media reports. It has been cited by more than 600 articles.
 In addition, I developed methodologies for GPCR crystallization. These include a pre-crystallization HT

LCP-FRAP technique and a fusion strategy to facilitate membrane protein crystallization in lipid mesophases (LCP).

July 2006-Apr 2009 Dept. of Cell Biology, TSRI
Research as Graduate Student with Advisor Francisco Asturias

 Single particle cryo-electron microscopy reconstruction of human RNA polymerase II complex.

Nov 2004-July 2006 Dept. of Biochemistry and Structural Biology, USTC
Research as Undergraduate with Advisors Maikun Teng and Liwen Niu

 Crystallization of yeast transcription elongation factor complex Spt4-Spt5NGN.AWARD & HONOR

Mar 2019

Jan 2019 Sept 2018 Jan 2018 Apr 2015

June 2014


“Outstanding Academic Leader” Award: From the Shanghai Science and Technology Commission to young scientists who take a lead in their respective academic field

“Director Award” and “Students’ Choice Award” for school year of 2018: FromiHuman Institute, ShanghaiTech University

Young Investigator (external member) at CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences

“Outstanding Teacher Award” for school year of 2017: From ShanghaiTechUniversity

“1000 Young Talents” Award: This is a prestigious award given by the CentralCommittee of China. Each year, only ~600 young scholars who have returned from abroad get this award in the entire country.

PuJiang Talents Award: From the Shanghai Science and Technology Commission to outstanding overseas Chinese who have returned to work in Shanghai

  1. Project leader for the Outstanding Academic Leader funding, 400,000¥, 2019.5-2022.4Goal: GPCR—from molecular structure to drug discovery
  2. Project leader for The NSFC-FRQS collaboration program, 81861128023, 3,000,000¥, 2019.1-2021.12.Goal: Structure-function and dynamics of the apelin receptor, a promising target for cardiovascular diseases
  3. Project leader for The National Key Research & Development Project, Project#4: 2018YFA0507004, Total 6,340,000¥, 2018.5-2023.4. Funded by Ministry of Science and Technology of the People’s Republic ofChina.
    Goal: GPCR small molecule ligand screening
  4. Project leader for the National Natural Sciece Foundation of China (NSFC) general program, 31670736, 600,000¥, 2017.1-2020.12
    Goal: Crystal structure and drug discovery opportunity for human apelin receptor
  1. Project leader for the 1000 Young Talents funding, 2,000,000¥, 2015.4-2018.3
  2. Project leader for the Pujiang Talents funding, 200,000¥, 2014.6-2016.5Goal: GPCR structure, function, and drug discovery


 Teaching (2018.7-2019.6):

  1. GPCR Biology and Drug DevelopmentCredit Hour: 21
  2. Industry PracticeCredit Hour: 16
  3. Biochemistry IICredit Hour: 24
  4. Huangmei OperaCredit Hour: 32
  5. Structural BiologyCredit Hour: 3

Total: 96

Elective course to Graduate Students Compulsory course to Undergraduate Students

Compulsory course to Undergraduate Students Elective course to Undergraduate & Graduate Students Elective course to Graduate Students

Curriculum Vitae

 Service (general):
Undergraduate & Graduate recruitment
ShanghaiTech oversea recruitment
Academic and education committee at SLST
Chair of Faculty search committee at iHuman
College Mentor for ShanghaiTech undergraduate students


 Publications:
a) Corresponding Author:


2. Yang Shifan, Wu Y, Xu T-H, Waal P.W, He Y, Pu M, Chen Y, DeBruine Z.J, Zhang B, Zaidi S.A, Popov P, Guo Y, Han G.W, Lu Y, Suino-Powell K, Dong S, Harikumar K.G, Miller L.J, Katritch V, Xu H.E, Shui W, Stevens R.C, Melcher K, Zhao S, Xu F*. “Crystal structure of Frizzled 4 receptor in ligand-free state” Nature, 560: 666 (2018)

3. Ma Yingli, Yue Y, Ma Y, Zhang Q, Zhou Q, Song Y, Shen Y, Li X, Ma X, Li C, Hanson MA, Han GW, Sickmier EA, Swaminath G, Zhao S, Stevens RC, Hu LA, Zhong W, Zhang M, Xu F*. “Structural Basis for Apelin Control of the Human Apelin Receptor” Structure, 8(6): 858 (2017)

Zhang Xianjun, Dong S-W, Xu F*. “Structural and Draggability Landscape of Frizzled G Protein-CoupledReceptors” Trends Biochem Sci, 43(12): 1033 (2018)


Curriculum Vitae

4. Zhang Xianjun, Zhao F, Wu Y, Yang J, Han GW, Zhao S, Ishchenko A, Ye L, Lin X, Ding K, Dharmarajan V, Griffin PR, Gati C, Nelson G, Hunter MS, Hanson MA, Cherezov V, Stevens RC, Tan W*, Tao H*, Xu F*.“Crystal structure of a multi-domain human smoothened receptor in complex with a super stabilizing ligand”Nature Communications, 8:15383 (2017)

5. Zhang Xianjun, Stevens R.C., Xu F*. “The importance of ligands for G protein-coupled receptor stability”Trends Biochem Sci, 40(1): 79-87 (2015)


b) 6.



8. Xu Fei, Liu W, Hanson M, Stevens R.C, Cherezov V. “Development of an Automated High ThroughputLCP-FRAP Assay to Guide Membrane Protein Crystallization in Lipid Mesophases” Crystal Growth & Design, 11(4): 1193-1201 (2011)

c) Co-Author:

9. Zhao Huan, Tian X, He L, Li Y, Pu W, Liu Q, Tang J, Wu J, Cheng X, Liu Y, Zhou Q, Tan Z, Bai F, Xu F,Smart N, Zhou B. “Apj+ Vessels Drive Tumor Growth and Represent a Tractable Therapeutic Target” Cell Reports, 25(5): 1241 (2018)

10. Ye Lintao, Ding K, Zhao F, Liu X, Wu Y, Liu Y, Xue D, Zhou F, Zhang X, Stevens, R.C., Xu F, Zhao S, Tao H. “A structurally guided dissection-then-evolution strategy for ligand optimization of smoothened receptor” Med. Chem. Commun., 8: 1332 (2017)

11. Liu Wei, Chun E, Thompson A.A, Chubukov P, Xu F, Katritch V, Han G-W, Roth C.B, Heitman L.H,Ijzerman A.P, Cherezov V, Stevens R.C. “Structural basis for allosteric regulation of GPCRs by sodiumions”Science, 337(6091): 232-236 (2012)

12. Chun Eugene, Thompson A.A, Liu W, Roth C.B, Griffith M.T., Katritch V, Kunken J, Xu F, Cherezov V,Hanson M.A, Stevens R.C. “Fusion Partner Toolchest for the Stabilization and Crystallization of G Protein-Coupled Receptors” Structure, 20(6): 967-976 (2012)

13. Tosh Dilip K., Phan K, Gao Z-G, Gakh A.A, Xu F, Deflorian F, Abagyan R, Stevens R.C, Jacobson K.A,Katritch V. “Optimization of Adenosine 5’-Carboxamide Derivatives as Adenosine Receptor Agonists Using Structure-Based Ligand Design and Fragment-Based Searching” J Med Chem, 55(9): 4297-4308 (2012)

14. Deflorian Francesca, Kumar TS, Phan K, Gao Z-G, Xu F, Wu H, Katritch V, Stevens R.C, Jacobson
K.A.“ Evaluation of Molecular Modeling of Agonist Binding in Light of the Crystallographic Structure of an Agonist-Bound A(2A) Adenosine Receptor” J Med Chem, 55(1): 538-552 (2012)

15. Guo Min, Xu F, Yamada J, Egelhofer T, Gao Y, Hartzog GA, Teng M, Niu L. “Core structure of the yeastSpt4-Spt5 complex: a conserved module for regulation of transcription elongation” Structure, 16:1649-1658 (2008)

First Author:
Xu Fei, Stevens R.C. “Trapping small caffeine in a large GPCR pocket” Structure, 19(9): 1204-1207


Xu Fei, Wu H, Katritch V, Han G-W, Jacobson K.A, Gao Z-G, Cherezov V, Stevens R.C. “Structure of anagonist-bound human A2A adenosine receptor” Science, 332: 322-327 (2011)


Curriculum Vitae

 International conference presentations:

  1. Xu F, “Structural insight into Frizzled GPCRs”. 17th Chinese Biophysics Congress. Tianjin, China (2019)
  2. Xu F, “Crystal structure of Frizzled 4 receptor in ligand-free state”. European Wnt Meeting. Heidelberg,

Germany (2018)

18. Xu F, “Crystal structure of a multi-domain human smoothened receptor”. QMB2017. Shanghai, China (2017)

19. Xu F, “New advances in structural discovery of human G protein-coupled receptors: the 826 project and importance of ligand stabilization”. ICCBM16. Praha, Czech Republic (2016)

20. Xu F, “The Structural Basis and Drug Discovery Opportunities in GPCRs”. 19th KPPS Symposium. Taean, Korea (2015)

21. Xu F, “Drug Discovery Opportunities in GPCRs”. 1st Annual Shanghai GPCR Forum. Shanghai, China (2013)

22. Xu F, Stevens R.C. “Structural characterization of adenosine A2A receptor with agonists and antagonists”Keystone Symposia: G Protein-Coupled Receptors. Breckenridge, Colorado, USA (2010)

23. Xu F, Asturias F.J. “Structural investigation of RNA polymerase II transcription initiation machinery”Workshop on Advanced Topics in EM Structure Determination. La Jolla, California, USA (2007)

 Patent Applications:
24. Hanson M.A, Roth C.B, Stevens R.C, Kunken J.M, Griffith M.T, Thompson A.A, Liu W, Xu F, Katritch V.“Novel fusion partners for the purpose of crystallizing G-Protein Coupled Receptors”. US20120288913 (2012)

25. Anke Kretz-Rommel et al, Xu F, et al. “Antibodies That Bind Human Cannabinoid 1 (CB1) Receptor”.US20170210797. RuiYi, Inc. (2017)

To be provided during the lecture.