全长LGR4-RSPOs复合体的冷EM结构和针对性纳米体用于抗肥胖治疗
Zhongyun Zhang1,2, Lu Wang3, Huarui Qiao3,4,5
1Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Nature communications
|September 25, 2025
概括
研究人员确定了氨酸丰富的重复含有G蛋白结合受体4 (LGR4) 作为肥胖的目标. 一种抑制性纳米体 (NB21) 阻断LGR4,促进脂肪色和减肥.
科学领域:
- 结构生物学是结构生物学.
- 分子药理学分子药理学
- 肥胖研究的研究.
背景情况:
- 肥胖是一个主要的健康问题,有效的治疗方法有限.
- 氨酸丰富的重复含有G蛋白结合受体4 (LGR4) 被确定为肥胖管理的潜在治疗标.
- 低温电子显微镜 (cryo-EM) 和深度测序的进步促进了新的药物发现方法.
研究的目的:
- 阐明LGR4与其配体和抑制剂相互作用的结构基础.
- 开发和描述一种针对LGR4的新型纳米体抑制剂,用于潜在的抗肥胖疗法.
- 在肥胖的临床前模型中研究LGR4向纳米体的治疗疗效.
主要方法:
- 使用冷电子显微镜 (cryo-EM) 来确定单独的LGR4的结构,以及与RSPO2和纳米体NB21的复合物.
- 开发一种抑制性纳米体 (NB21),旨在阻止RSPO与LGR4.4结合.
- 实验室试验评估了NB21-mFc对Wnt信号的抑制及其对白色脂肪细胞中线粒体呼吸和热生成的影响.
- 在体内研究评估了NB21-mFc在饮食诱导和遗传 (ob/ob) 肥胖模型中的疗效,包括评估白脂肪色和能量消耗.
主要成果:
- 确定了单独LGR4,LGR4-RSPO2和LGR4-NB21复合物的冷EM结构,提供了详细的分子见解.
- 纳米体NB21是为了有效抑制LGR4-RSPO相互作用而开发的.
- NB21-mFc证明了Wnt标志性信号通路的抑制,导致色脂肪细胞中增强的线粒体呼吸和热生成.
- 在体内给药NB21-mFc促进了白色脂肪的色,增加了能量消耗,并赋予了对肥胖的抵抗力.
- LGR4 缺陷取消了NB21-mFc的抗肥胖作用,证实了标的作用.
结论:
- 结构研究揭示了LGR4-RSPO和LGR4-NB21复合体内的关键相互作用.
- 一种新的LGR4向纳米体 (NB21) 有效抑制LGR4信号传递,并通过增强热生成促进减肥.
- 这项研究为开发基于LGR4的纳米体疗法用于治疗肥胖症提供了坚实的基础.
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