葡萄糖受体与葡萄糖类似物复合的结构
Haonan Zhang1,2,3, Anna Qiao1,2,3, Linlin Yang4
1CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai 201203, China.
Nature
|January 5, 2018
概括
我们确定了与葡萄糖类似物结合的人类葡萄糖受体 (GCGR) 的结构. 这揭示了关键的分子相互作用和GCGR激活的新模型,进步了对B类G蛋白结合受体 (GPCR) 的理解.
科学领域:
- 结构生物学
- 分子药理学
- 生物化学
背景情况:
- 乙类G蛋白结合受体 (GPCR) 对于荷尔蒙平衡至关重要,是治疗点.
- 现有的模型表明联体结合B类GPCR的细胞外域 (ECD) 和细胞外膜域 (TMD).
- 之前的结构研究在分辨率和形状灵活性方面存在局限性,使分子相互作用变得模两可.
研究的目的:
- 阐明人类葡萄糖受体 (GCGR) 与其联体之间的分子相互作用.
- 为B类GPCR激活提供高分辨率的结构洞察力.
- 提出一个更新的GCGR激活模型.
主要方法:
- 人体全长葡萄糖受体 (GCGR) 与葡萄糖类似物 (NNC1702) 复合的X射线晶体.
- 对受体的细胞外域 (ECD),膜外域 (TMD),茎区域和细胞外环中的结构变化的分析.
- 与以前确定的非活性GCGR复合物的结构进行比较.
主要成果:
- 确定了与葡萄糖类似物结合的全长人体GCGR的3.0 Å分辨率晶体结构.
- 揭示了GCGR和联体之间的详细分子相互作用.
- 在茎和第一个细胞外环中观察到显著的形状变化,形成关键结相互作用.
- 与不活跃状态相比,发现了GCGR ECD和TMD之间的明显相对方向.
结论:
- 该结构提供了前所未有的GCGR-相互作用的分子细节.
- 为GCGR激活提出了一种双结合位点触发模型,涉及茎,细胞外环和TMD的结构变化.
- 该模型扩展了B类GPCR已建立的双域结合模型,并提供了对受体激活机制的见解.
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