在塔基基宁NK1和NK2受体中的解密特异性和交叉反应性
Jesper J Madsen1, Jacob E Petersen2, Dan P Christensen3
1Global and Planetary Health, College of Public Health, University of South Florida, Tampa, Florida, USA; Center for Global Health and Infectious Diseases Research, College of Public Health, University of South Florida, Tampa, Florida, USA; Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA.
The Journal of biological chemistry
|November 9, 2023
概括
了解太基宁受体 (NK1R,NK2R) 的特异性揭示了连接体如何结合. 与受体循环和N端段的相互作用解释了天然配体的强度和交叉反应性,有助于药物开发.
科学领域:
- 药理学和分子生物学
- G蛋白结合受体 (GPCR) 研究研究
- 药物的发现和开发.
背景情况:
- 神经素1受体 (NK1R) 和神经素2受体 (NK2R) 是针对药物开发的GPCR.
- 这些受体分别与物质P和神经素A结合,但表现出交叉反应性.
- 一个常见的C端序列 (Phe-X-Gly-Leu-Met-NH2) 影响了连接体功能.
研究的目的:
- 阐明结构-活性关系,控制NK1R和NK2R的联结和特异性.
- 了解自然联结体对强效激活和观察到的交叉反应的分子基础.
- 为开发新型NK1R和NK2R激动剂或对抗剂提供见解.
主要方法:
- 研究了联结受体复合体的结构-活性关系.
- 使用突变和嵌合体受体和连接体结构.
- 分析了联体氨基酸与特定受体区域 (ECL2,N端段) 之间的相互作用.
主要成果:
- 干特异性和交叉反应性是由FxGLM动机之前的相互作用决定的.
- 关键的相互作用涉及细胞外循环2 (ECL2) β-hairpin和跨膜螺旋1的N端段.
- 在ECL2中,带正电荷的侧链 (NK1R中的R177,NK2R中的K180) 是至关重要的;N端位1-3是不可用的.
结论:
- 详细的分子相互作用解释了NK1R和NK2R配体的特异性和交叉反应性.
- 突变分析证实了特定受体和连接体区域在确定结合中的作用.
- 这些发现支持了针对塔基宁受体的改进治疗剂的合理设计.
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