一个雄激素膜受体的识别,结构和激素设计
Zhao Yang1, Yu-Qi Ping2, Ming-Wei Wang3
1Key Laboratory Experimental Teratology of the Ministry of Education, New Cornerstone Science Laboratory, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, and Advanced Medical Research Institute, NHC Key Laboratory of Otorhinolaryngology, Qilu hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, China.
Cell
|January 30, 2025
概括
在肌肉细胞中激活GPR133膜受体,通过增加循环AMP (cAMP) 来增强强度. 这一发现为与雄激素相关的生理学提供了新的治疗途径.
科学领域:
- 内分泌学
- 分子生物学
- 结构生物学
背景情况:
- 雌激素通过核雌激素受体 (AR) 和潜在未知的膜受体调节生理功能.
- 调解雄激素作用的特定膜受体仍然在很大程度上没有特征.
研究的目的:
- 识别和描述新型的雌激素膜受体.
- 阐明雄激素与已识别的膜受体结合的结构基础.
- 探索针对肌肉相关疾病的治疗策略.
主要方法:
- 用5α-二激素 (5α-DHT) 在肌肉细胞中激活GPR133的测定.
- 测量细胞内循环AMP (cAMP) 的水平.
- 低温电子显微镜 (cryo-EM) 用于对GPR133-Gs复合物的结构分析.
- 在GPR133小分子调节器的选中.
主要成果:
- 5α-DHT激活肌肉细胞中的GPR133膜受体,从而增加cAMP和增强肌肉力量.
- 化EM揭示了GPR133识别5α-DHT和甲醇 (MET) 的结构基础,突出了粘附性GPCR (aGPCR) 中的保留动机.
- 一个小分子AP503被确定激活GPR133,将肌肉增强效应与AR介导的副作用分开.
结论:
- GPR133被确定为参与肌肉生理学的功能性雄激素膜受体.
- 这些结构见解为理解aGPCRs对类固醇激素的识别提供了基础.
- 用像AP503这样的分子准GPR133为增强肌肉力量和解决与雄激素相关的疾病提供了一个有前途的治疗策略.
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