Transport mechanism and structural pharmacology of human urate transporter URAT1  

作　　者：Yaxin Dai Chia-Hsueh Lee 

机构地区：[1]Department of Structural Biology,St.Jude Children’s Research Hospital,Memphis,TN,USA

出　　处：《Cell Research》2024年第11期776-787,共12页细胞研究（英文版）

基　　金：supported by National Institutes of Health grants(R01GM143282 and R01NS133147);C.-H.L.and Y.D.are supported by ALSAC.

摘　　要：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.

关 键 词：URATE ANION mechanism 

分 类 号：O62[理学—有机化学]