课题组PI简介
刘合力,北京大学医学部药学院研究员,博士生导师,国家自然基金优秀青年基金获得者 (2013),国家海外高层次人才计划“青年项目”获得者(2012),北京大学优秀青年人才“百人计划”入选者(2011);美国西北大学Feinberg医学院分子药理学与生物化学系,博士后、Research associate
(2006~2011);中国科学院生物物理研究所,生物化学与分子生物学博士 (2005);Elsevier 期刊Current Research in
Pharmacology and Drug Discovery和《中国药学》英文版的编委会成员。长期致力于细胞表面受体的信号转导结构机制和靶向药物研究。以第一作者或者通讯作者身份在Cell、Nature
Communications、PNAS、EMBO. J、J Autoimmun.、JBC、FEBS letters 等期刊发表了多篇研究论文;受邀在Current
Opinion in Structural Biology上发表综述1篇;申请蛋白质类候选药物的国家发明专利2项(其中一项已经获得授权;另一项为选择性识别致癌突变KIT
ITD的靶向单克隆抗体);获得了国家海外高层次人才计划、国家自然基金优秀青年基金、3个国家自然基金面上项目和1个北京市自然基金面上项目等资助。
课题组网页:http://222.28.103.88/labhome/ (限于北医校园网用户)
研究介绍
细胞表面受体是全球60%药物的作用靶标,且蕴藏着癌症、神经精神类疾病等诸多重大疾病的药物靶标而亟待发现和确证。探讨潜在药物靶标的结构与功能关系,是精准调控它们功能的基础,是药物靶标确证不可或缺的重要步骤。本课题组将结构生物学技术与传统的药理学研究方法相结合,力图形成有自己特色的研究方向,即“细胞表面受体的分子和结构药理学”,旨在探讨细胞表面受体跨膜信号转导的结构机制、基于结构机制发现调节受体功能的分子工具(小分子化合物、单抗、蛋白质)、为癌症或自闭症等神经精神类疾病确证新的药物靶标,以此助力于原创性(first-in-class)“精准药物”的发现。
至今,本课题组着力于受体酪氨酸激酶(receptor tyrosine
kinases, RTKs;如KIT、CSF1R、PDGFRa、ROR2)、受体酪氨酸磷酸酶(receptor-type protein
tyrosine phosphatases, RPTPs;如PTPD)、神经粘连受体(CASPR2、ADAM22、neurexin、neurofascin)、粘连型G蛋白偶联受体(LPHN3、BAI3、FSHR)、整合素以及具有GAP(GTPase激活蛋白)活性的Plexin等受体信号转导的结构机制研究和靶标确证。近期,我们揭示了孤独症相关的突触样黏附分子-5(synaptic
adhesion-like molecule 5,SALM5)结合位于突触前膜的受体酪氨酸磷酸酶PTPD而介导突触分化的结构机制(Nature Commun. 2018 Jan 18; 9(1):268;Current Opinion in Structural Biology.
2019 Feb 8; 54:59-67),并拟基于结构机制挖掘调节LAR-RPTP家族受体信号转导的分子工具。我们根据此前获得的第三类RTK受体的信号转导机制【KIT/SCF(Liu & Chen et al., EMBO J. 2007 26(3):891-901), PDGFb/PDGFRb (An & Liu
et al., PNAS 2010 107(25):11307-12), CSF1/FMS (Chen et al., PNAS,
2008 105(47):18267-72) 以及IL34/FMS
(Liu et al., Biochim Biophys Acta. 2012 1824(7):938-45)】而设计合适的抗原用于免疫小鼠,用传统杂交瘤技术获得了可以选择性识别受体酪氨酸激酶致癌性突变体KIT ITD的单克隆抗体3G2,运用蛋白质晶体学技术揭示了3G2选择性识别KIT ITD的结构基础,并申请了国家发明专利(201810588853.X)。该发明首次在活体水平证实KIT ITD可以驱动肿瘤的发生,并确证了KIT ITD可以作为胃肠道间质瘤等癌症的药物靶标。
代表性论文
·
1. Liu H*. Synaptic organizers:
synaptic adhesion-like molecules (SALMs). Current Opinion in Structural Biology. 2019 Feb 8; 54:59-67.
(Invited review) (hereinafter *corresponding author)
·
2. Liang W#, Zhang J#, Saint-Martin M#, Xu
F, Noraz N, Liu J, Honnorat J*, Liu H*. Structural mapping of hot spots
within human CASPR2 discoidin domain for autoantibody recognition. J Autoimmun. 2019 Jan; 96:168-177
(#equal contribution)
·
3. Liu J, Zhang J, Xu F, Lin Z, Li Z, Liu
H*. Structural characterizations of human periostin dimerization and
cysteinylation. FEBS Lett.
2018 Jun; 592(11):1789-1803 (FEBS Letters Highlights
2018)
·
4. Lin Z, Liu J, Ding H, Xu F, Liu H*.
Structural basis of SALM5-induced PTPδ dimerization for synaptic
differentiation. Nature Commun.
2018 Jan 18; 9(1):268
·
5. Bu Q, Li Z, Zhang J, Xu F, Liu J, Liu
H*. The crystal structure of full-length Sizzled from Xenopus laevis yields
insights into Wnt-antagonistic function of secreted Frizzled-related proteins. J Biol Chem. 2017 Sep 29;
292(39):16055-16069
·
6. Jiang X*, Fischer D, Chen X, McKenna SD, Liu
H, Sriraman V, Yu HN, Goutopoulos A, Arkinstall S, He X. Evidence for
follicle-stimulating hormone receptor as a functional trimer. J Biol Chem. 2014 May
16;289(20):14273-82
·
7. Jiang X*, Liu H, Chen X, Chen PH,
Fischer D, Sriraman V, Yu HN, Arkinstall S, He X. Structure of
follicle-stimulating hormone in complex with the entire ectodomain of its
receptor. Proc Natl Acad Sci U S A.
2012 Jul 31; 109(31):12491-6
·
8. Liu H, Leo C, Chen X, Wong BR,
Williams LT, Lin H, He X*. The mechanism of shared but distinct CSF-1R
signaling by the non-homologous cytokines IL-34 and CSF-1. Biochim Biophys Acta. 2012 Jul;
1824(7):938-45
·
9. Liu H, Focia PJ, He X*. Homophilic
adhesion mechanism of neurofascin, a member of the L1 family of neural cell
adhesion molecules, Journal of
Biological Chemistry, 2011.1.7, 286(1): 797-805
·
10. Liu H,
Juo ZS, Shim AH, Focia PJ, Chen X, Garcia KC, He X*. Structural basis of
Semaphorin-Plexin recognition and viral mimicry from Sema7A and A39R complexes
with PlexinC1. Cell. 2010 Sep
3; 142(5):749-61 (Commented by F1000)
·
11. Shim AH#, Liu
H#, Chen X, Lin PC, He X*. Structures of a platelet-derived growth
factor/propeptide complex and a platelet-derived growth factor/receptor
complex. Proc Natl Acad Sci U S A.
2010 Jun 22; 107(25): 11307-12 (#equal contribution)
·
12. Liu H,
Shim AH, He X*. Structural characterization of the ectodomain of a
disintegrin and metalloproteinase-22 (ADAM22), a neural adhesion receptor instead
of metalloproteinase: INSIGHTS ON ADAM FUNCTION, Journal of Biological Chemistry, 2009.10.16, 284(42):
29077-29086 (selected as Papers of the
Week)
·
13. Chen X, Liu
H, Focia PJ, Shim AH, He X. Structure
of macrophage colony stimulating factor bound to FMS: diverse signaling
assemblies of class III receptor tyrosine kinases. Proc Natl Acad Sci U S A. 2008 Nov 25;105(47):18267-72
·
14. Chen X, Liu H, Shim AH, Focia PJ, He
X.Chen X, et al. Structural basis for synaptic adhesion mediated by
neuroligin-neurexin interactions. Nature
Struct Mol Biol. 2008 Jan;15(1):50-6.
·
15. Liu H#, Chen X#, Focia PJ,
He X*. Structural basis for stem cell factor-KIT signaling and
activation of class III receptor tyrosine kinases, The EMBO Journal, 2007.2.7, 26(3): 891-901 (#equal
contribution)
专利
·
1. 刘合力、黄国龙等,一种提高白介素IL-34热力学稳定性的方法,中国发明专利授权号 ZL2016102555350.1
·
2. 刘合力、丁焕弟等, 一种选择性识别KIT ITD致癌性突变的单克隆抗体及其应用,中国发明专利申请号 201810588853.X
招聘招生
1、招聘博士后:欢迎神经/肿瘤生物学或药理学、低温电镜结构生物学的博士(毕业0-5年)来合作开展高水平研究,待遇从优。2、招生:欢迎有志于在结构水平研究生物医学规律或追求原创性药物发现的研究生、本科生来学习。E-mail: liuheli(AT)hsc.pku.edu.cn [(AT) = @]; Tel:
86-10-82801227。