Cyclosporine A sterically inhibits statin transport by solute carrier OATP1B1.

IF 4 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Biological Chemistry Pub Date : 2025-04-06 DOI:10.1016/j.jbc.2025.108484

Min Woo Sung, Kuan Hu, Lea M Hurlimann, Joshua A Lees, Kimberly F Fennell, Mark A West, Chester Costales, Amilcar David Rodrigues, Iwan Zimmermann, Roger J P Dawson, Shenping Liu, Seungil Han

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引用次数: 0

Abstract

Members of the Organic Anion Transporter Polypeptides (OATP) are integral membrane proteins responsible for facilitating the transport of organic anions across the cell membrane. OATP1B1 (SLCO1B1), the prototypic OATP family member, is the most abundant uptake transporter in the liver and key mediator of the hepatic uptake and clearance of numerous endogenous and xenobiotic compounds. It serves as a locus of important drug-drug interactions, such as those between statins and cyclosporine A, and carries the potential to enable liver-targeting therapeutics. In this study, we report cryo-EM structures of OATP1B1 and its complexes with one of its statin substrates, atorvastatin, and an inhibitor, cyclosporine A. This structural analysis has yielded insights into the mechanisms underlying OATP1B1-mediated transport of statins and the inhibitory effect of cyclosporine A. These findings contribute to a better understanding of the molecular processes involved in drug transport and offer potential avenues for the development of targeted medications for liver-related conditions.

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环孢素A通过溶质载体OATP1B1立体抑制他汀类药物的转运。

有机阴离子转运多肽（OATP）的成员是负责促进有机阴离子在细胞膜上运输的完整膜蛋白。OATP1B1 （SLCO1B1）是OATP家族的原型成员，是肝脏中最丰富的摄取转运蛋白，也是肝脏摄取和清除许多内源性和外源性化合物的关键介质。它是重要的药物-药物相互作用的位点，例如他汀类药物和环孢素a之间的相互作用，并且具有实现肝脏靶向治疗的潜力。在这项研究中，我们报道了OATP1B1及其与他汀类底物之一阿托伐他汀和抑制剂的复合物的低温电镜结构。这项结构分析揭示了oatp1b1介导的他汀类药物转运和环孢素a的抑制作用的机制。这些发现有助于更好地理解药物转运的分子过程，并为开发针对肝脏相关疾病的靶向药物提供了潜在的途径。

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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来源期刊

Journal of Biological Chemistry Biochemistry, Genetics and Molecular Biology-Biochemistry

自引率

4.20%

发文量

1233

期刊介绍： The Journal of Biological Chemistry welcomes high-quality science that seeks to elucidate the molecular and cellular basis of biological processes. Papers published in JBC can therefore fall under the umbrellas of not only biological chemistry, chemical biology, or biochemistry, but also allied disciplines such as biophysics, systems biology, RNA biology, immunology, microbiology, neurobiology, epigenetics, computational biology, ’omics, and many more. The outcome of our focus on papers that contribute novel and important mechanistic insights, rather than on a particular topic area, is that JBC is truly a melting pot for scientists across disciplines. In addition, JBC welcomes papers that describe methods that will help scientists push their biochemical inquiries forward and resources that will be of use to the research community.