作為最晚被發(fā)現(xiàn)的EGFR家族成員,，ErbB4在生理以及病理上都有著獨(dú)特之處,，是重要癌癥藥物靶標(biāo)，亦與精神分裂癥相關(guān)。中科院上海藥物研究所研究員蔣華良和副研究員陽懷宇帶領(lǐng)研究生杜蕓利用分子動力學(xué)(MD)模擬,，對ErbB4胞外區(qū)的配體激活機(jī)制進(jìn)行了細(xì)致的探究,。
表皮生長因子受體（Epidermal Growth Factor Receptor, EGFR）家族酪氨酸激酶受體在細(xì)胞生長和分化等過程中發(fā)揮基礎(chǔ)性作用，是眾多疾病的重要藥物靶點(diǎn),。此前,，EGFR家族蛋白功能實(shí)現(xiàn)的動態(tài)機(jī)制并未被充分闡明，人們對其生理和病理功能機(jī)制的認(rèn)識因此受到了限制,。
通過時間長達(dá)微秒尺度的常規(guī)MD模擬,，他們捕捉到了ErbB4胞外區(qū)在配體誘導(dǎo)下由“非激活”狀態(tài)到“類激活”狀態(tài)的大規(guī)模構(gòu)象變化，分析了配體在這一變化過程中的作用,，并且構(gòu)建了構(gòu)象轉(zhuǎn)化的能量面,。根據(jù)計算得出的ErbB4構(gòu)象變化主要能壘（2.7kcal/mol）與實(shí)驗測定的同家族成員EGFR構(gòu)象變化能壘（1-2kcal/mol）非常吻合，并且計算得到的穩(wěn)定構(gòu)象與同家族成員晶體結(jié)構(gòu)也高度一致,。
根據(jù)計算結(jié)果,，研究人員提出了ErbB4胞外區(qū)的激活機(jī)制，為ErbB4及其他家族成員的激活機(jī)制研究提供了新的思路,。相關(guān)研究也為針對胞外區(qū)構(gòu)象變化開展藥物設(shè)計奠定了基礎(chǔ),。
4月19日，該項研究成果以全文形式發(fā)表于《美國化學(xué)會志》（JACS）,，并被選為封面文章,。
該研究項目得到了國家重大科學(xué)研究計劃和國家自然科學(xué)基金的資助。（生物谷Bioon.com）
doi:10.1021/ja211941d
PMC:
PMID:
Conformational Transition and Energy Landscape of ErbB4 Activated by Neuregulin1β: One Microsecond Molecular Dynamics Simulations
Yun Du, Huaiyu Yang, Yechun Xu, Xiaohui Cang, Cheng Luo, Yanyan Mao, Yuanyuan Wang, Guangrong Qin, Xiaomin Luo, and Hualiang Jiang
ErbB4, a receptor tyrosine kinase of the ErbB family, plays crucial roles in cell growth and differentiation, especially in the development of the heart and nervous system. Ligand binding to its extracellular region could modulate the activation process. To understand the mechanism of ErbB4 activation induced by ligand binding, we performed one microsecond molecular dynamics (MD) simulations on the ErbB4 extracellular region (ECR) with and without its endogenous ligand neuregulin1β (NRG1β). The conformational transition of the ECR-ErbB4/NRG1β complex from a tethered inactive conformation to an extended active-like form has been observed, while such large and function-related conformational change has not been seen in the simulation on the ECR-ErbB4, suggesting that ligand binding is indeed the active inducing force for the conformational transition and further dimerization. On the basis of MD simulations and principal component analysis, we constructed a rough energy landscape for the conformational trans...
