G蛋白偶联受体(GPCR)是一类具有七次跨膜螺旋的膜蛋白受体,它们感知多种不同胞外信号,调节细胞对环境的反应。其配体包括激素、神经递质、趋化因子等。目前已上市的药物约三分之一靶向GPCR。在过去的十多年,针对GPCR的结构生物学研究取得了巨大的进展,但是对GPCR-G蛋白特异性识别的机理,GPCR偏向性信号传导的机理尚不清楚。本实验室关注与疾病相关的重要GPCR的结构生物学研究,以及基于结构的药物设计。另外,我们也关注新的GPCR药物筛选方法的研发。
科学贡献
揭示了别构药物调节β2肾上腺素受体功能的分子机理,为GPCR的别构药物研发提供了结构基础和理论指导。
提出了GPCR-G蛋白复合物形成过程的动态模型。
研究成果
1、鉴定出β2肾上腺素受体的首个胞内别构激动剂结合位点和首个胞内别构拮抗剂拮抗位点,阐明了别构药物调节β2肾上腺素受体功能的分子机理。( Science, 2019. Nature, 2017)
2、揭示GPCR和G蛋白复合物形成过程中可能的中间状态结构,并在同一工作中开发了一种通过融合G蛋白羧基端肽段来稳定GPCR激活态结构的新方法。( Cell, 2019)
3、基于M2和M3乙酰胆碱受体配体结合口袋单个氨基酸的区别,改进一个不具有亚型选择性的药物,使之获得对M3乙酰胆碱受体的高选择性。( PNAS, 2018)
4、解析第一个重金属转运P型ATP酶(铜泵)的高分辨率晶体结构,揭示铜离子跨膜转运的分子机理。( Nature, 2011)
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