4.5 Article

Molecular basis for selective uptake and elimination of organic anions in the kidney by OAT1

期刊

出版社

NATURE PORTFOLIO
DOI: 10.1038/s41594-023-01039-y

关键词

-

向作者/读者索取更多资源

The kidney in mammals maintains blood homeostasis by selectively taking up, retaining or eliminating toxins, drugs and metabolites. Organic anion transporters (OATs) are responsible for recognizing and excreting metabolites and toxins in the nephron. Inhibition of OATs is therapeutically used to enhance drug efficacy and reduce nephrotoxicity. This study presents cryogenic-electron microscopy structures of OAT1 bound to alpha-ketoglutarate, tenofovir, and probenecid, providing molecular insights into alpha-ketoglutarate driven drug elimination and the allosteric regulation of organic anion transport by chloride in the kidney.
In mammals, the kidney plays an essential role in maintaining blood homeostasis through the selective uptake, retention or elimination of toxins, drugs and metabolites. Organic anion transporters (OATs) are responsible for the recognition of metabolites and toxins in the nephron and their eventual urinary excretion. Inhibition of OATs is used therapeutically to improve drug efficacy and reduce nephrotoxicity. The founding member of the renal organic anion transporter family, OAT1 (also known as SLC22A6), uses the export of alpha-ketoglutarate (alpha-KG), a key intermediate in the Krebs cycle, to drive selective transport and is allosterically regulated by intracellular chloride. However, the mechanisms linking metabolite cycling, drug transport and intracellular chloride remain obscure. Here, we present cryogenic-electron microscopy structures of OAT1 bound to alpha-KG, the antiviral tenofovir and clinical inhibitor probenecid, used in the treatment of Gout. Complementary in vivo cellular assays explain the molecular basis for a-KG driven drug elimination and the allosteric regulation of organic anion transport in the kidney by chloride.

作者

我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。

评论

主要评分

4.5
评分不足

次要评分

新颖性
-
重要性
-
科学严谨性
-
评价这篇论文

推荐

暂无数据
暂无数据