通过冷-EM与Gαs复合的人类腺环酶9的结构洞察
Risa Nomura1, Shota Suzuki1, Koki Nishikawa2
1Cellular and Structural Physiology Laboratory (CeSPL), Advanced Research Initiative, Institute of Science Tokyo, 1-5-45 Yushima Bunkyo-ku, Tokyo 113-8510, Japan.
Journal of structural biology
|June 4, 2025
概括
研究人员确定了与Gαs结合的人类腺环酶9 (AC9) 的结构,揭示了其激活机制. 这项研究确定了跨膜域作为AC9相关疾病的潜在药物标.
科学领域:
- 生物化学 生化学
- 结构生物学 结构生物学
- 分子药理学分子药理学
背景情况:
- 基环酶9 (AC9) 对于生理功能至关重要,产生循环AMP (cAMP),由G蛋白结合受体 (GPCR) 信号调节.
- AC9的激活涉及Gαs结合,这是细胞信号通路的关键过程.
- 虽然牛的AC9结构已知,但人类的AC9 (hAC9) 结构和激活机制仍然未被阐明,阻碍了药物开发.
研究的目的:
- 使用冷电子显微镜 (cryo-EM) 单独和与Gαs (hAC9-Gαs) 组合确定人类AC9 (hAC9) 的高分辨率结构.
- 阐明hAC9被Gαs激活的结构基础及其cAMP生成功能.
- 在hAC9结构中识别潜在的新药标.
主要方法:
- 使用单粒子冷电子显微镜 (cryo-EM) 分析hAC9和hAC9-Gαs复合体.
- 结构在高分辨率下得到分辨:hAC9-Gαs的可溶性域2.7 Å,hAC9-Gαs的跨膜 (TM) 域3.4 Å,单独hAC9的3.2 Å.
- 进行了生物化学和生物物理分析,以了解结构影响.
主要成果:
- 冷电磁分析揭示了hAC9激活的关键结构特征.
- Gαs 结合会诱导可溶域中的显著构造变化,从而打开催化部位.
- 精确确定了封闭催化部位的C端位置,并意外地确定了TM域中的链密度.
结论:
- 确定的结构为hAC9的激活机制及其在cAMP生产中的作用提供了前所未有的洞察力.
- 在TM域中鉴定出一条链表明它有可能成为一种全调节部位和一种新型药物标.
- 这些发现为针对AC9和相关酶的基于结构的药物发现奠定了基础.
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