近日，美国圣裘德儿童研究医院Chia-Hsueh Lee及其研究小组，报道了人尿酸转运蛋白URAT1的转运机制及结构药理学研究。2024年9月9日出版的《细胞研究》发表了这项成果。

据悉，尿酸盐是肝脏嘌呤代谢的内源性产物。血液中尿酸水平过高会导致痛风，这是一种非常常见和痛苦的炎症性关节炎。排泄的尿酸盐主要通过URAT1转运蛋白在肾脏中重新吸收，而URAT1转运蛋白是抗痛风药物的关键靶点。

为了揭示尿酸盐转运和药物抑制的机制，研究人员用尿酸盐、反阴离子吡嗪酸盐或不同化学型的抗痛风药物(lesinurad、verinurad和dotinurad)测定了人URAT1的低温电镜结构。

研究人员捕获了URAT1在尿酸摄取过程中由外到内的转变，揭示了尿酸结合在富含苯丙氨酸的口袋中，并与关键的门控残基结合以驱动运输循环。与尿酸盐的单一结合位点不同，吡嗪酸盐与URAT1中三个不同的功能相关位点相互作用，这一机制尚未在其他阴离子反转运蛋白中观察到。

此外，虽然这三种药物都与底物竞争并停止转运周期，但verinurad和dotinurad进一步劫持了门控残基，从而实现了更高的效力。这些见解深化了他们对有机阴离子转运的理解，并为设计改进的痛风治疗药物奠定了基础。

附：英文原文

Title: Transport mechanism and structural pharmacology of human urate transporter URAT1

Author: Dai, Yaxin, Lee, Chia-Hsueh

Issue&Volume: 2024-09-09

Abstract: Urate is an endogenous product of purine metabolism in the liver. High urate levels in the blood lead to gout, a very common and painful inflammatory arthritis. Excreted urate is reabsorbed in the kidney mainly by URAT1 antiporter, a key target for anti-gout drugs. To uncover the mechanisms of urate transport and drug inhibition, we determined cryo-EM structures of human URAT1 with urate, counter anion pyrazinoate, or anti-gout drugs of different chemotypes — lesinurad, verinurad, and dotinurad. We captured the outward-to-inward transition of URAT1 during urate uptake, revealing that urate binds in a phenylalanine-rich pocket and engages with key gating residues to drive the transport cycle. In contrast to the single binding site for urate, pyrazinoate interacts with three distinct, functionally relevant sites within URAT1, a mechanism that has not yet been observed in other anion antiporters. In addition, we found that while all three drugs compete with substrates and halt the transport cycle, verinurad and dotinurad further hijack gating residues to achieve high potency. These insights advance our understanding of organic anion transport and provide a foundation for designing improved gout therapeutics.

DOI: 10.1038/s41422-024-01023-1

Source: https://www.nature.com/articles/s41422-024-01023-1