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导师介绍

孙金鹏 教授


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孙金鹏 研究员

国家杰出青年基金获得者(药理学,2018年)

 新基石项目研究员(2023年)

北京大学医学部生理学与病理生理学系教授、生物物理系系主任


研究方向

1. GPCR的配体发现及互作机制

2. GPCR在糖尿病等代谢类疾病、生殖、听觉、肾脏疾病和骨发育中的作用机制和靶向性药物发展

3. GPCR偏好性信号转导的药理学理论

4. 组织再造过程中的跨膜信号转导


教育经历:

1993年-1998年,中国科学技术大学 生命科学院生物学,计算机科学,双学士

1998年-2001年,中国科学技术大学 生命科学院,硕士

2001年-2007年,阿尔伯特.爱因斯坦医学院/Albert Einstein College of Medicine 博士,导师,张仲寅(Zhong-yin, Zhang)

2007年-2011年,杜克大学/Duke University 博士后 导师 Robert j. Lefkowitz; James B. (杜克大学药物及生物化学教授,美国科学院院士,邵逸夫奖获得者2007,美国自然科学奖获得者2008,HHMI,2012诺贝尔奖获得者。)


长期从事膜受体G蛋白偶联受体(GPCR)的相关研究,聚焦于GPCR功能多样性的细胞机制以及针对GPCR的药物发展,发展了Arrestin所介导的GPCR偏向性信号转导的药理学理论,阐明了GPCR偏向性在胰岛素分泌和糖代谢中的调控功能,并开发了系列偏向性干预策略。主要发现如下:

(1)发现了GPR97是糖皮质激素的膜受体,介导糖皮质激素的快速信号转导,从而为陈宜张教授早年发现的糖皮质激素非核受体功能提供了重要的理论支持 ;鉴定了粘附类受体GPR126内源性配体孕酮和17-OHP,阐明孕酮可以通过激活GPR126促进三阴性乳腺癌的发生和发展;首次发现血管紧张素受体的内源性别构调节因子COMP及高同半胱氨酸可以直接激活AT1R等(Nature 2021,PNAS 2022,Cell Research 2021, Nature Commun 2017, Nature Commun 2021);(2)创新性地提出了GPCR磷酸化编码的“笛子模型”(Nature Commun 2015,Faculty 1000专题评论, Nature Commun 2021, PNAS 2021),多聚脯氨酸码头分选及别构建调控理论 (Nature Chem Biol 2018),以及证明了配体依赖的受体7次跨膜核心可以对Arrestin功能的指导(Nature Commun 2020,Faculty 1000专题评论),并可应用新模式发展磷酸酶抑制剂,从而有效地操控受体的磷酸化编码的新理念(Cell Research 2014,Cell Reports 2016,获2014年Cell Research的专题评论),为GPCR的偏向性药物开发奠定了理论基础;

(3)解析了GPCR感知痒觉,力学以及多种配体的编码机制。揭示了痒觉受体识别多种配体的机制以及独特的激活模式,阐明了痒感觉得重要机制,完美地解决了该领域多年以来的困惑,这项研究无疑为瘙痒的治疗提供了广阔的发展前景。(Nature. 2021;600(7887):164-169)以黏附受体作为模型进行功能和结构的分析,用实验证明了受体感知机械力后通过Stachel序列激活受体,并进一步确定了Stachel中的5个疏水氨基酸组成的保守HIM(Fss-03xφφφxφss-09)在Stachel序列与受体相互作用中起着核心作用,并据此机制发展了黏附类受体通用多肽激动剂和拮抗剂(Nature. 2022a, Proof received on 2022/03/25; Nature. 2022b, Proof received on 2022/03/17)

(4)发现了GPCR区域性信号转导中Arrestin偏好性激活离子通道的一种非G蛋白依赖的全新快速机制,打破了人们对GPCR信号转导的固有认识(Nature Commun 2017(杂志专题评论);Nature Commun 2018);揭示了黏附类受体在顶膜区域信号转导对重吸收的调控作用(Elife 2018, Faculty 1000专题评论);

(5)阐明了多个GPCR对胰岛功能,糖代谢和体外组织再造的调控作用,为进一步靶向GPCR偏向性信号途径的药物设计提供了指导(Cell Metabolism 2022,同期杂志preview专题评论;Biol Psychiatry 2017,封面文章,Faculty 1000专题评论, Diabetologia 2014,Br J Pharmacol 2015);

(6)阐明了快乐激素多巴胺受体以及肝肠轴枢纽胆汁酸受体识别其内源性配体,及偏好性信号转导的结构基础 以及痒觉感知的分子机制 (Nature 2020,2021, Cell 2021, 封面文章);(7)建立了靶向GPCR偏向性信号途径的Aptamer和小分子抑制剂的开发方法,获得了一系列GPCR的偏好性配体以及GPCR下游磷酸酶的特异性抑制剂(Future Med Chem 2015,J Med Chem 2014)。

目前以通讯作者在Nature(7篇),Science (1篇,封面), Cell(2篇,1篇封面),Nature Metabolism(1篇),Cell Metabolism(1篇),Nat Chem Biol(3篇),Cell Research(2篇),PNAS(6篇),Nat Commun(7篇)等SCI收录杂志发表80余篇文章,并在国际和国内学术大会做特邀报告,产生广泛学术影响。曾获新基石研究员项目资助(2023年)、国家杰出青年基金(2018年)、谈家桢生命科学创新奖(2022年)、中华医学科技奖-医学科学技术二等奖(2022年)、第三届全国创新争先奖(2023年)等。目前主持科技部重点研发项目、国家自然科学基金重点项目和面上项目、北京市重点项目等多项基金。


主要代表作:

1. Shang P, Rong NK, Jiang JJ, Cheng J, Zhang MH, Kang DW, Qi L, Guo LL, Yang GM, Liu Q, Zhou ZZ, Li XB, Zhu KK, Meng QB, Han X, Yan WQ, Kong YL, Yang LJ, Wang XH, Lei DP, Feng X, Liu XY, Yu X, Wang Y#, Li Q#, Shao ZH#, Yang F#, Sun JP#. Structural and signaling mechanism of TAAR1 enabled preferential agonist design. Cell. (IF 64.5) 2023

2. Xu Z, Guo L, Yu JJ,Shen SY,Wu C, Zhang WF, Zhao C, Deng Y, Tian XW, Feng YY, Hou HL, Su LT, Wang HS, Guo S, Wang HL, Wang KX, Chen PP, Zhao J, Zhang XY, Yong XH, Cheng L, Liu LX, Yang SY, Yang F, Wang XH, Yu X#, Xu YF#, Sun JP#, Yan W#, Shao ZH#. Ligand recognition and G-protein coupling of trace amine receptor TAAR1. Nature. IF 64.82023

3. Guo L, Cheng J, Lian S, Liu Q, Lu Y, Zheng Y, Zhu K, Zhang M, Kong Y, Zhang C, Rong N, Zhuang Y, Fang G, Jiang J, Zhang T, Han X, Liu Z, Xia M, Liu S, Zhang L, Liberles SD, Yu X, Xu Y#, Yang F#, Li Q#, Sun JP#. Structural basis of amine odorant perception by a mammal olfactory receptor. Nature. IF 64.8 2023 Jun;618(7963):193-200. 通讯作者

4. Mao C, Xiao P, Tao XN, Qin J, He QT, Zhang C, Guo SC, Du YQ, Chen LN, Shen DD, Yang ZS, Zhang HQ, Huang SM, He YH, Cheng J, Zhong YN, Shang P, Chen J, Zhang DL, Wang QL, Liu MX, Li GY, Guo Y, Xu HE, Wang C, Zhang C, Feng S#, Yu X#, Zhang Y#, Sun JP#. Unsaturated bond recognition leads to biased signal in a fatty acid receptor. Science. IF 56.9 2023 Apr 7;380(6640):eadd6220.通讯作者

5. Ping YQ, Xiao P, Yang F, Zhao RJ, Guo SC, Yan X, Wu X, Zhao FH, Zhou FL, Xi YT, Yin WH, He FD, Zhang DL, Zhu ZL, Jiang Y, Torsten Schöneberg, Ines Liebscher#, Xu H. Eric#, Sun JP#. Structural basis for the tethered peptide activation of adhesion GPCRs. Nature. IF 64.8. 2022. 2022 Apr;604(7907):763-770. 通讯作者

6. Yang F, Guo L, Li Y, Wang G, Wang J, Zhang C, Fang GX, Chen X, Liu L, Yan X, Liu Q, Qu C, Xu Y, Xiao P, Zhu Z, Li Z, Zhou J, Yu X, Gao N#, Sun JP#. Structure, function and pharmacology of human itch receptor complexes. Nature. IF 64.8 2021 Dec;600(7887):164-169. 通讯作者

7. Ping YQ, Mao C, Xiao P, Zhao RJ, Jiang Y, Yang Z, An WT, Shen DD, Yang F, Zhang H, Qu C, Shen Q, Tian C, Li ZJ, Li S, Wang GY, Tao X, Wen X, Zhong YN, Yang J, Yi F, Yu X, Xu HE#, Zhang Y#, Sun JP#. Structures of the glucocorticoid-bound adhesion receptor GPR97-Go complex. Nature. IF 64.8 2021 Jan;589(7843):620-626. 通讯作者 (获得Faculty 1000推荐)

8. Xiao P, Guo S, Wen X, He QT, Lin H, Huang SM, Gou L, Zhang C, Yang Z, Zhong YN, Yang CC, Li Y, Gong Z, Tao XN, Yang ZS, Lu Y, Li SL, He JY, Wang C, Zhang L#, Kong L#, Sun JP#, Yu X#. Tethered peptide activation mechanism of the adhesion GPCRs ADGRG2 and ADGRG4. Nature. IF 64.8 2022 Apr;604(7907):771-778. 通讯作者

9. Yang F, Mao C, Guo L, Lin J, Ming Q, Xiao P, Wu X, Shen Q, Guo S, Shen DD, Lu R, Zhang L, Huang S, Ping Y, Zhang C, Ma C, Zhang K, Liang X, Shen Y, Nan F, Yi F, Luca VC, Zhou J, Jiang C, Sun JP#, Xie X#, Yu X#, Zhang Y#. Structural basis of GPBAR activation and bile acid recognition. Nature. IF 64.8 2020 Nov;587(7834):499-504. 通讯作者

10. Xiao P, Yan W, Gou L, Zhong YN, Kong L, Wu C, Wen X, Yuan Y, Cao S, Qu C, Yang X, Yang CC, Xia A, Hu Z, Zhang Q, He YH, Zhang DL, Zhang C, Hou GH, Liu H, Zhu L, Fu P, Yang S, Rosenbaum DM, Sun JP#, Du Y#, Zhang L#, Yu X#, Shao Z#. Ligand recognition and allosteric regulation of DRD1-Gs signaling complexes. Cell. IF 64.5 2021 Feb 18;184(4):943-956.e18. 通讯作者 (封面文章,专题推荐)

11. Yan Z, Wang JY, Yang F, Zhu KK, Wang PG, Guan Y, Ning SL, Lu Y, Li Y, Zhang C, Zheng Y, Zhou SH, Wang XW, Wang MW, Xiao P,Yi F, Zhang C, Zhang PJ, Xu F, Liu BH, Zhang H,Yu X #, Gao N#, Sun JP#.Cryo-EM structure of the X-linked acrogigantism-related orphan GPR101-Gs complex enabled identification of ligands with rejuvenating potential. Nat Chem Biol.IF 14.8 2023 accept. 通讯作者

12. Lin H, Xiao P, Bu RQ, Guo S, Yang Z, Yuan D, Zhu ZL, Zhang CX, He QT, Zhang C, Ping YQ, Zhao RJ, Ma CS, Liu CH, Zhang XN, Jiang D, Huang S, Xi YT, Zhang DL, Xue CY, Yang BS, Li JY, Lin HC, Zeng XH, Zhao H, Xu WM, Yi F#, Liu Z#, Sun JP#, Yu X#. Structures of the ADGRG2-Gs complex in apo and ligand-bound forms. Nat Chem Biol.IF 14.8 2022 Nov;18(11):1196-1203. 通讯作者

13. Yang F, Xiao P, Qu CX, Liu Q, Wang LY, Liu ZX, He QT, Liu C, Xu JY, Li RR, Li MJ, Li Q, Guo XZ, Yang ZY, He DF, Yi F, Ruan K, Shen YM, Yu X, Sun JP#, Wang JY#. Allosteric mechanisms underlie GPCR signaling to SH3-domain proteins through arrestin. (IF 14.8) Nat Chem Biol 2018 Sep;14(9):876-886. 通讯作者

14. Cheng J, Yang Z, Ge XY, Gao MX, Meng R, Xu X, Zhang YQ, Li RZ, Lin JY, Tian ZM, Wang J, Ning SL, Xu YF, Yang F, Gu JK, Sun JP#, Yu X#. Autonomous sensing of the insulin peptide by an olfactory G protein-coupled receptor modulates glucose metabolism. Cell Metab. (IF 29.0) 2022 Feb 1;34(2):240-255. 通讯作者

15. Wang JL, Dou XD, Cheng j, Gao MX, Xu GF, Ding W, Ding JH, Li y, Wang SH, Ji ZW, Zhao XY, Huo TY, Zhang CF, Liu YM, Sha XY, Gao JR, Zhang WH, Hao Y, Zhang C, Sun JP#, Jiao N# and Yu X#. Functional screening and rational design of compounds targeting GPR132 to treat diabetes. Nat Metab. (IF 20.1) 2023 accept. 通讯作者

16. Chen Y, Mao C, Gu R, Zhao R, Li W, Ma Z, Jia Y, Yu F, Luo J, Fu Y, Sun J#, Kong W#. Nidogen-2 is a Novel Endogenous Ligand of LGR4 to Inhibit Vascular Calcification. Circ Res.IF 20.1 2022 Dec 2;131(12):1037-1054. 通讯作者

17. An W, Lin H, Ma L, Zhang C, Zheng Y, Cheng Q, Ma C, Wu X, Zhang Z, Zhong Y, Wang M, He D, Yang Z, Du L, Feng S, Wang C, Yang F, Xiao P#, Zhang P#, Yu X#, Sun JP#. Progesterone activates GPR126 to promote breast cancer development via the Gi pathway. Proc Natl Acad Sci USA. IF 11.1. 2022 Apr 12;119(15):e2117004119. 通讯作者

18. Huang SM, Xiong MY, Liu L, Mu J, Wang MW, Jia YL, Cai K, Tie L, Zhang C, Cao S, Wen X, Wang JL, Guo SC, Li Y, Qu CX, He QT, Cai BY, Xue C, Gan S, Xie Y, Cong X, Yang Z, Kong W, Li S, Li Z, Xiao P, Yang F, Yu X, Guan YF, Zhang X#, Liu Z#, Yang BX#, Du Y#, Sun JP#. Single hormone or synthetic agonist induces Gs/Gi coupling selectivity of EP receptors via distinct binding modes and propagating paths. Proc Natl Acad Sci U S A.IF 11.1 2023 Jul 25;120(30):e2216329120 通讯作者

19. Wang MW, Yang Z, Chen X, Zhou SH, Huang GL, Sun JN, Jiang H, Xu WM#, Lin HC#, Yu X#, Sun JP#. Activation of PTH1R alleviates epididymitis and orchitis through Gq and β-arrestin-1 pathways. Proc Natl Acad Sci U S A.IF 11.1 2021 Nov 9;118(45):e2107363118. 通讯作者

20. Qu CX, Park JY, Yun MW, He QT, Yang F, Kin K, Han D, Li R, T.M.Iverson, V V.Gurevich , Sun JP#, Chung KY#. Scaffolding mechanism of arrestin-2 in the cRaf/MEK1/ERK signaling cascade. Proc Natl Acad Sci U S A.IF 11.12021 Sep 14;118(37):e2026491118. 通讯作者

21. Ma L, Yang F, Wu X, Mao C, Guo L, Miao T, Zang SK, Jiang X, Shen DD, Wei T, Zhou H, Wei Q, Li S, Shu Q, Feng S, Jiang C, Chu B, Du L#, Sun JP#, Yu X#, Zhang Y#, Zhang P#. Structural basis and molecular mechanism of biased GPBAR signaling in regulating NSCLC cell growth via YAP activity. Proc Natl Acad Sci U S A.IF 11.1 2022 Jul 19;119(29):e2117054119. 通讯作者

22. Fu Y, Huang Y, Yang Z, Chen Y, Zheng J, Mao C, Li Z, Liu Z, Yu B, Li T, Wang M, Xu C, Zhou Y, Zhao G, Jia Y, Guo W, Jia X, Zhang T, Li L, Liu Z, Guo S, Ma M, Zhang H, Liu B, Du J, Wang W, Tang C, Gao P, Xu Q, Wang X, Liu J, Sun JP#, Kong W#. Cartilage oligomeric matrix protein is an endogenous β-arrestin-2-selective allosteric modulator of AT1 receptor counteracting vascular injury. Cell Res. (IF 20.396) 2021 Jul;31(7):773-790. 通讯作者

23. Wang HM, Xu YF, Ning SL, Yang DX, Li Y, Du YJ, Yang F, Zhang Y, Liang N, Yao W, Zhang LL, Gu LC, Gao CJ, Pang Q, Chen YX, Xiao KH, Yu X#, Sun JP#. The catalytic region and PEST domain of PTPN18 distinctly regulate the HER2 phosphorylation and ubiquitination barcodes. Cell Research. (IF 20.396) 2014 Sep;24(9):1067-90. 通讯作者 (获得同期文章的专题评论)

24. Guo L, Zhang Y, Fang G, Tie L, Zhuang Y, Xue C, Liu Q, Zhang M, Zhu K, You C, Xu P, Yuan Q, Zhang C, Liu L, Rong N, Peng S, Liu Y, Wang C, Luo X, Lv Z, Kang D, Yu X, Zhang C, Jiang Y, Dong X, Zhou J#, Liu Z#, Yang F#, Eric Xu H#, Sun JP#. Ligand recognition and G protein coupling of the human itch receptor MRGPRX1. Nat Commun. (IF 16.6) 2023 Aug 17;14(1):5004. 通讯作者

25. He QT, Xiao P, Huang SM, Jia YL, Zhu ZL, Lin JY, Yang F, Tao XN, Zhao RJ, Gao FY, Niu XG, Xiao KH, Wang J#, Jin C#, Sun JP#, Yu X#. Structural studies of phosphorylation-dependent interactions between the V2R receptor and arrestin-2. Nat Commun. (IF 13.691). 2021 Apr 22;12(1):2396. 通讯作者

26. Liu Q, He QT, Lyu X, Yang F, Zhu ZL, Xiao P, Yang Z, Zhang F, Yang ZY, Wang XY, Sun P, Wang QW, Qu CX, Gong Z, Lin JY, Xu Z, Song SL, Huang SM, Guo SC, Han MJ, Zhu KK, Chen X, Kahsai AW, Xiao KH, Kong W, Li FH, Ruan K, Li ZJ, Yu X, Niu XG, Jin CW, Wang J#, Sun JP#. DeSiphering receptor core-induced and ligand-dependent conformational changes in arrestin via genetic encoded trimethylsilyl 1H-NMR probe.Nat Commun. (IF 13.691) 2020 Sep 25;11(1):4857.通讯作者(获得Faculty 1000推荐)

27. Li T, Yu B, Liu Z, Li J, Ma M, Wang Y, Zhu M, Yin H, Wang X, Fu Y, Yu F, Wang X, Fang X, Sun JP#, Kong W#. Homocysteine directly interacts and activates the angiotensin II type I receptor to aggravate vascular injury. Nat Commun. (IF 13.691) 2018 Jan 2;9(1):11. 通讯作者

28. Liu CH, Gong Z, Liang Zl, Liu ZX, Yang F, Sun YJ, Ma ML, Wang YJ, Xiao KH, Zhou Z, Yu X#, Sun JP#. Arrestin biased GPCR agonism induces acute catecholamine secretion through TRPC3 coupling. Nat Commun. (IF 13.691) 2017 Feb 9;8:14335. 通讯作者 (获得Channels杂志的专题评论,Channels (Austin). 2017 May 1:1-3.)

29. Yang F, Yu X, Liu C, Qu CX, Gong Z, Liu HD, Li FH, Wang HM, He DF, Yi F, Song C, Tian CL, Xiao KH, Wang JY#, Sun JP#. Phospho-selective mechanisms of arrestin conformations and functions revealed by unnatural amino acid incorporation and 19F-NMR. Nat Commun. (IF 13.691) 2015 Sep 8;6:8202. 通讯作者 (获得Faculty 1000推荐)

30. Lu S#, He X, Yang Z, Chai Z, Zhou S, Wang J, Rehman AU, Ni D, Pu J, Sun JP#, Zhang J#. Activation pathway of a G protein-coupled receptor uncovers conformational intermediates as targets for allosteric drug design. Nat Commun. (IF 13.691) 2021 Aug 5;12(1):4721. 通讯作者

31. Dong JH, Wang YJ, Cui M, Wang XJ, Zheng WS, Ma ML, He DF, Hu QX, Zhang DL, Ning SL, Liu CH, Wang C, Wang Y, Li XY, Lin A, Kahsai A, Cahill III T, Chen ZY, Yu X, Sun JP#. Adaptive activation of a stress response pathway improves learning and memory through Gs and β-arrestin-1 regulated lactate metabolism. Biol Psychiatry. (IF 12.069) 2017 Apr 15;81(8):654-670. 通讯作者(获得Faculty 1000推荐,封面文章)

32. Qu CX, Mao CY, Xiao P, Shen QY, Zhong YN, Yang F, Shen DD, Tao XN, Zhang HB, Yan X, Zhao RJ, He JY, Guan Y, Zhang C, Hou GH, Zhang PJ, Hou GG, Li ZJ, Yu X, Chai RJ#, Guan YF, Sun JP#, Zhang Y#. Ligand recognition, unconventional activation and G protein coupling of the prostaglandin E2 receptor 2 (EP2). Science Advances (IF 13.116) 2021 Apr 2;7(14):eabf1268. 通讯作者

33. Guan Y, Du HB, Yang Z, Wang YZ, Ren R, Liu WW, Zhang C, Zhang JH, An WT, Li NN, Zeng XX, Li J, Sun YX, Wang YF, Yang F, Yang J, Xiong W, Yu X, Chai RJ, Tu XM#, Sun JP#, Xu ZG#. Deafness-Associated ADGRV1 Mutation Impairs USH2A Stability through Improper Phosphorylation of WHRN and WDSUB1 Recruitment. Adv Sci (Weinh). (IF 15.1) 2023 Jun;10(16):e2205993. 通讯作者

34. Lin JY, Cheng J, Du YQ, Pan W, Zhang Z, Wang J, An J, Yang F, Xu YF, Lin H, An WT, Wang J, Yang Z, Chai RJ, Sha XY, Hu H.L#, Sun JP#, Yu X#. In vitro expansion of pancreatic islet clusters facilitated by hormones and chemicals. Cell Discov. (IF 10.56) 2020 Apr 7;6:20. 通讯作者

35. Zhang H, Xiao P, Wong YT, Shen W, Chhabra M, Peltier R, Jiang Y, He Y, He J, Tan Y, Xie Y, Ho D, Lam YW#, Sun JP#, Sun HY#. Construction of an alkaline phosphatase-specific two-photon probe and its imaging application in living cells and tissues. Biomaterials. (IF 12.47) 2017 Sep;140:220-229.通讯作者


联系方式:

孙金鹏

北京大学医学部生理与病理生理系

Email: sunjinpeng@bjmu.edu.cn 或者 sunjinpengsdu@126.com

电话:01082805639