在神经Y1受体的配体结合模式的结构基础
Zhenlin Yang1,2, Shuo Han1,3, Max Keller4
1Chinese Academy of Sciences Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Nature
|April 20, 2018
概括
研究人员确定了与抗体结合的神经Y (NPY) Y1受体的晶体结构. 这揭示了NPY受体对抗剂和激动剂如何结合,有助于发现治疗肥胖和癌症的药物.
科学领域:
- 结构生物学
- 药理学
- 神经科学
背景情况:
- 神经Y (NPY) 受体对于调节食物摄入量,焦虑和癌症至关重要.
- Y1受体 (Y1R) 是治疗肥胖,瘤和骨质损失的关键目标.
- 现有的Y1R抗体面临的挑战包括低效和低生物可用性.
研究的目的:
- 阐明Y1R对抗剂和激动剂结合的结构基础.
- 为开发更好的Y1R向治疗提供见解.
主要方法:
- 人类Y1R与抗体UR-MK299和BMS-193885的X射线结晶学.
- 突变性研究以确定结合因子的决定因素.
- 分子对接,核磁共振,光交叉连接,以及对激素结合的功能测试.
主要成果:
- 在高分辨率下确定Y1R与两个选择性抗剂的晶体结构.
- 揭示了各种对抗剂的结合方式和影响连体选择性的因素.
- 提供了内源NPY激动剂结合的见解,包括N端相互作用.
结论:
- 结构和功能数据阐明了Y1R-连接物相互作用.
- 这些发现有助于基于结构的NPY受体调节剂的药物设计.
- 能够为NPY受体相关疾病开发更有效的治疗方法.
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