表皮生长因子受体的结构与计算生物学研究进展
Progress in Structural and Computational Studies of Epidermal Growth Factor Receptor
DOI: 10.12677/biphy.2013.11002, PDF, HTML, XML, 下载: 3,375  浏览: 13,579  科研立项经费支持
作者: 张泳辉：中国科学技术大学生命科学学院；张志勇*：合肥微尺度物质科学国家实验室(筹)，合肥
关键词: 表皮生长因子受体；结构与功能；计算机模拟；分子动力学模拟；构象变化；Epidermal Growth Factor Receptor (EGFR); Structure and Function; Computer Modeling; Molecular Dynamics Simulations; Conformational Changes
摘要: 表皮生长因子受体(epidermal growth factor receptor: EGFR)在细胞信号转导中发挥了重要作用，调节细胞的增殖、分化与迁移。EGFR与多种癌症密切相关，这使其成为一个理想的抗肿瘤药物靶点。本文对EGFR的结构生物学及计算生物学的研究进展做一综述。通过结构生物学家的不懈努力，已经对EGFR的三维空间结构有了较为清晰的认识。计算机模拟是研究生物大分子动态过程的重要手段之一，可以在EGFR静态结构的基础上，模拟其在配体诱导的激活过程中发生的大尺度、长时程的动态构象变化。对EGFR的结构及其分子内部运动的研究，有助于揭示其发挥生物学功能的分子机理，为抗肿瘤药物的设计开发提供指导。
Abstract: Epidermal growth factor receptor (EGFR) plays a critical role in the network of signal transduction, and regulates cell proliferation, differentiation, and migration. EGFR is implicated in different kinds of cancers, which makes it an excellent target for anti-tumor therapy. This review considers structural and computational studies of EGFR, and their impact on our understanding of EGFR function. With continuing efforts of biologists, many high-resolution structures of different regions in EGFR, which include the extracellular region and the intracellular tyrosine kinase do-main, have been solved. Starting from these structures, computer simulation techniques enable us to investigate large length-scale and long time-scale conformational changes during the EGFR activation. All the studies will be helpful to reveal the molecular mechanism in EGFR regulation, and provide valuable knowledge for developing anti-cancer drugs.
文章引用：张泳辉, 张志勇. 表皮生长因子受体的结构与计算生物学研究进展[J]. 生物物理学, 2013, 1(1): 11-16. http://dx.doi.org/10.12677/biphy.2013.11002

参考文献

[1] Nicholson RI, Gee JM, Harper ME: EGFR and cancer prognosis. Eur J Cancer, 2001, 37(Suppl 4):9-15.
[2] Ogiso H, Ishitani R, Nureki O, Fukai S, Yamanaka M, Kim JH, Saito K, Sakamoto A, Inoue M, Shirouzu M et al: Crystal structure of the complex of human epidermal growth factor and receptor extracellular domains. Cell, 2002, 110(6):775-787.
[3] Garrett TPJ, McKern NM, Lou M, Elleman TC, Adams TE, Lovrecz GO, Zhu HJ, Walker F, Frenkel MJ, Hoyne PA et al: Crystal structure of a truncated epidermal growth factor receptor extracellular domain bound to transforming growth factor α. Cell, 2002, 110(6):763-773.
[4] Ferguson KM, Berger MB, Mendrola JM, Cho HS, Leahy DJ, Lemmon MA: EGF activates its receptor by removing interactions that autoinhibit ectodomain dimerization. Mol cell, 2003, 11(2):507-517.
[5] Burgess AW, Cho HS, Eigenbrot C, Ferguson KM, Garrett TPJ, Leahy DJ, Lemmon MA, Sliwkowski MX, Ward CW, Yokoyama S: An open-and-shut case? Recent insights into the activation of EGF/ErbB receptors. Mol cell, 2003, 12(3):541-552.
[6] Dawson JP, Berger MB, Lin CC, Schlessinger J, Lemmon MA, Ferguson KM: Epidermal growth factor receptor dimerization and activation require ligand-induced conformational changes in the dimer interface. Mol Cell Biol, 2005, 25(17):7734-7742.
[7] Lu C, Mi LZ, Grey MJ, Zhu J, Graef E, Yokoyama S, Springer TA: Structural evidence for loose linkage between ligand binding and kinase activation in the epidermal growth factor receptor. Mol Cell Biol, 2010, 30(22):5432-5443.
[8] Alvarado D, Klein DE, Lemmon MA: Structural basis for negative cooperativity in growth factor binding to an EGF receptor. Cell, 2010, 142(4):568-579.
[9] Wood ER, Truesdale AT, McDonald OB, Yuan D, Hassell A, Dickerson SH, Ellis B, Pennisi C, Horne E, Lackey K et al: A unique structure for epidermal growth factor receptor bound to GW572016 (Lapatinib): relationships among protein conformation, inhibitor off-rate, and receptor activity in tumor cells. Cancer Res ,2004, 64(18):6652-6659.
[10] Zhang X, Gureasko J, Shen K, Cole PA, Kuriyan J: An allosteric mechanism for activation of the kinase domain of epidermal growth factor receptor. Cell, 2006, 125(6):1137-1149.
[11] Ferguson KM: Structure-based view of epidermal growth factor receptor regulation. Annu Rev Biophys, 2008, 37:353-373.
[12] Kastner J, Loeffler HH, Roberts SK, Martin-Fernandez ML, Winn MD: Ectodomain orientation, conformational plasticity and oligomerization of ErbB1 receptors investigated by molecular dynamics. J Struct Biol, 2009, 167(2):117-128.
[13] Tynan CJ, Roberts SK, Rolfe DJ, Clarke DT, Loeffler HH, Kastner J, Winn MD, Parker PJ, Martin-Fernandez ML: Human epidermal growth factor receptor (EGFR) aligned on the plasma membrane adopts key features of Drosophila EGFR asymmetry. Mol Cell Biol, 2011, 31(11):2241-2252.
[14] Zhang Z, Wriggers W: Polymorphism of the epidermal growth factor receptor extracellular ligand binding domain: the dimer interface depends on domain stabilization. Biochemistry, 2011, 50(12):2144-2156.
[15] Papakyriakou A, Vourloumis D, Tzortzatou-Stathopoulou F, Karpusas M: Conformational dynamics of the EGFR kinase domain reveals structural features involved in activation. Proteins, 2009, 76(2):375-386.
[16] Shan Y, Eastwood MP, Zhang X, Kim ET, Arkhipov A, Dror RO, Jumper J, Kuriyan J, Shaw DE: Oncogenic mutations counteract intrinsic disorder in the EGFR kinase and promote receptor dimerization. Cell, 2012, 149(4):860-870.

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