Molecular basis for selective uptake and elimination of organic anions in the kidney by OAT1.
Molecular basis for selective uptake and elimination of organic anions in the kidney by OAT1.
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DOI：
10.1038/s41594-023-01039-y
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发表时间：
2023-11
影响因子：
16.8
通讯作者：
Newstead, Simon
中科院分区：
文献类型：
--
作者：
Parker, Joanne L.;Kato, Takafumi;Kuteyi, Gabriel;Sitsel, Oleg;Newstead, Simon
在哺乳动物中，肾脏通过选择性摄取、保留或消除毒素、药物和代谢物在维持血液稳态方面发挥重要作用。有机阴离子转运蛋白（OAT）负责识别肾单位中的代谢物和毒素，并最终将其排泄到尿液中。OAT的抑制在治疗上用于提高药物疗效和降低肾毒性。肾脏有机阴离子转运蛋白家族的创始成员OAT 1（也称为SLC 22 A6）使用α-酮戊二酸（α-KG）（克雷布斯循环中的关键中间体）的输出来驱动选择性转运，并受细胞内氯的变构调节。然而，代谢循环，药物转运和细胞内氯离子的机制仍然不清楚。在这里，我们展示了与α-KG结合的OAT 1的低温电子显微镜结构，α-KG是抗病毒的替诺福韦和临床抑制剂丙磺舒，用于治疗痛风。补充性体内细胞试验解释了α-KG驱动药物消除的分子基础和氯离子对肾脏中有机阴离子转运的变构调节。有机阴离子转运蛋白1（OAT 1）结构揭示了肾脏中代谢物、药物和毒素选择性摄取和消除的分子基础。
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 α-ketoglutarate (α-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 α-KG, the antiviral tenofovir and clinical inhibitor probenecid, used in the treatment of Gout. Complementary in vivo cellular assays explain the molecular basis for α-KG driven drug elimination and the allosteric regulation of organic anion transport in the kidney by chloride. Organic anion transporter 1 (OAT1) structures reveal the molecular basis for the selective uptake and elimination of metabolites, drugs and toxins in the kidney.
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DOI：
10.1107/s0907444909029436
发表时间：
2009-10-01
影响因子：
2.2
作者：
Moriarty, Nigel W.;Grosse-Kunstleve, Ralf W.;Adams, Paul D.
通讯作者：
Adams, Paul D.
影响因子：
64.8
作者：
Jumper J;Evans R;Pritzel A;Green T;Figurnov M;Ronneberger O;Tunyasuvunakool K;Bates R;Žídek A;Potapenko A;Bridgland A;Meyer C;Kohl SAA;Ballard AJ;Cowie A;Romera-Paredes B;Nikolov S;Jain R;Adler J;Back T;Petersen S;Reiman D;Clancy E;Zielinski M;Steinegger M;Pacholska M;Berghammer T;Bodenstein S;Silver D;Vinyals O;Senior AW;Kavukcuoglu K;Kohli P;Hassabis D
通讯作者：
Hassabis D
DOI：
10.1107/s2059798317003382
发表时间：
2017-03-01
期刊：
Acta crystallographica. Section D, Structural biology
影响因子：
--
作者：
Emsley P
通讯作者：
Emsley P
影响因子：
5.7
作者：
Fowler, Philip W.;Orwick-Rydmark, Marcella;Radestock, Sebastian;Solcan, Nicolae;Dijkman, Patricia M.;Lyons, Joseph A.;Kwok, Jane;Caffrey, Martin;Watts, Anthony;Forrest, Lucy R.;Newstead, Simon
通讯作者：
Newstead, Simon
影响因子：
64.8
作者：
Enomoto, A;Kimura, H;Endou, H
通讯作者：
Endou, H