Sung Min Woo, Hu Kuan, Hurlimann Lea M, Lees Joshua A, Fennell Kimberly F, West Mark A, Costales Chester, Rodrigues Amilcar David, Zimmermann Iwan, Dawson Roger J P, Liu Shenping, Han Seungil
Discovery Sciences, Discovery & Early Development, Pfizer Inc, Groton, Connecticut, USA.
Linkster Therapeutics AG, Zurich, Switzerland.
J Biol Chem. 2025 May;301(5):108484. doi: 10.1016/j.jbc.2025.108484. Epub 2025 Apr 6.
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 a 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 the 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.
有机阴离子转运多肽（OATP）成员是负责促进有机阴离子跨细胞膜转运的整合膜蛋白。OATP1B1（SLCO1B1）是OATP家族的典型成员，是肝脏中最丰富的摄取转运蛋白，也是众多内源性和外源性化合物肝脏摄取和清除的关键介质。它是重要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，并具有实现肝脏靶向治疗的潜力。在本研究中，我们报告了OATP1B1及其与一种他汀类底物阿托伐他汀和一种抑制剂环孢素A的复合物的冷冻电镜结构。这种结构分析深入了解了OATP1B1介导的他汀类药物转运机制以及环孢素A的抑制作用。这些发现有助于更好地理解药物转运所涉及的分子过程，并为开发针对肝脏相关疾病的靶向药物提供了潜在途径。
