人类有机阳离子转运体 1 转运和抑制的结构研究。

IF 13 1区 生物学 Q1 CELL BIOLOGY Cell Discovery Pub Date : 2024-03-15 DOI:10.1038/s41421-024-00664-1
Shuhao Zhang, Angqi Zhu, Fang Kong, Jianan Chen, Baoliang Lan, Guodong He, Kaixuan Gao, Lili Cheng, Xiaoou Sun, Chuangye Yan, Ligong Chen, Xiangyu Liu
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摘要

人类有机阳离子转运体 1 (hOCT1),又称 SLC22A1,是肝脏摄取结构多样的内源性和外源性有机阳离子不可或缺的部分,影响着代谢和药物的药代动力学。值得注意的是,二甲双胍作为治疗 2 型糖尿病的一线药物,是一种重要的 hOCT1 底物。相反,hOCT1 也会受到诸如螺内酯(醛固酮受体的类固醇类似物抑制剂)等药物的抑制,因此在开发新的药物治疗时,有必要深入了解 hOCT1 与药物之间的相互作用。尽管进行了广泛的研究,但在分子水平上,hOCT1转运和抑制机制的具体细节仍然难以捉摸。在这里,我们展示了hOCT1-二甲双胍复合物在三种不同构象状态(外向开放、外向闭锁和内向闭锁)下的冷冻电镜结构,以及部分开放和完全开放状态下的无底物hOCT1。我们还展示了 hOCT1 与螺内酯复合物的外向和内向构象。这些结构从原子水平上揭示了二甲双胍通过 hOCT1 的动态转移过程以及螺内酯的抑制机制。此外,我们还发现了对 hOCT1 以及其他 SLC22 家族转运体构象灵活性至关重要的 "YER "基序。我们的发现极大地促进了对 hOCT1 分子功能的了解,并为设计针对这种转运体的新治疗药物提供了一个基础框架。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Structural insights into human organic cation transporter 1 transport and inhibition.

The human organic cation transporter 1 (hOCT1), also known as SLC22A1, is integral to hepatic uptake of structurally diversified endogenous and exogenous organic cations, influencing both metabolism and drug pharmacokinetics. hOCT1 has been implicated in the therapeutic dynamics of many drugs, making interactions with hOCT1 a key consideration in novel drug development and drug-drug interactions. Notably, metformin, the frontline medication for type 2 diabetes, is a prominent hOCT1 substrate. Conversely, hOCT1 can be inhibited by agents such as spironolactone, a steroid analog inhibitor of the aldosterone receptor, necessitating a deep understanding of hOCT1-drug interactions in the development of new pharmacological treatments. Despite extensive study, specifics of hOCT1 transport and inhibition mechanisms remain elusive at the molecular level. Here, we present cryo-electron microscopy structures of the hOCT1-metformin complex in three distinct conformational states - outward open, outward occluded, and inward occluded as well as substrate-free hOCT1 in both partially and fully open states. We also present hOCT1 in complex with spironolactone in both outward and inward facing conformations. These structures provide atomic-level insights into the dynamic metformin transfer process via hOCT1 and the mechanism by which spironolactone inhibits it. Additionally, we identify a 'YER' motif critical for the conformational flexibility of hOCT1 and likely other SLC22 family transporters. Our findings significantly advance the understanding of hOCT1 molecular function and offer a foundational framework for the design of new therapeutic agents targeting this transporter.

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来源期刊
Cell Discovery
Cell Discovery Biochemistry, Genetics and Molecular Biology-Molecular Biology
CiteScore
24.20
自引率
0.60%
发文量
120
审稿时长
20 weeks
期刊介绍: Cell Discovery is a cutting-edge, open access journal published by Springer Nature in collaboration with the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences (CAS). Our aim is to provide a dynamic and accessible platform for scientists to showcase their exceptional original research. Cell Discovery covers a wide range of topics within the fields of molecular and cell biology. We eagerly publish results of great significance and that are of broad interest to the scientific community. With an international authorship and a focus on basic life sciences, our journal is a valued member of Springer Nature's prestigious Molecular Cell Biology journals. In summary, Cell Discovery offers a fresh approach to scholarly publishing, enabling scientists from around the world to share their exceptional findings in molecular and cell biology.
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