Structural basis for the transport and substrate selection of human urate transporter 1

• Published in: Cell reports (Cambridge) Vol. 43; no. 8; p. 114628
• Main Authors: He, Jingjing, Liu, Guoyun, Kong, Fang, Tan, Qiulong, Wang, Zhenzhou, Yang, Meng, He, Yonglin, Jia, Xiaoxiao, Yan, Chuangye, Wang, Chao, Qian, Hongwu
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 27-08-2024; Elsevier
• Subjects: Biological Transport; CP: Molecular biology; cryo-EM; Cryoelectron Microscopy; HEK293 Cells; Humans; Models, Molecular; OAT4; Organic Anion Transporters - chemistry; Organic Anion Transporters - metabolism; Organic Anion Transporters, Sodium-Independent; Organic Cation Transport Proteins - chemistry; Organic Cation Transport Proteins - metabolism; Substrate Specificity; URAT1; urate transporter; Uric Acid - metabolism; CP: Molecular biology; urate transporter; URAT1; cryo-EM; OAT4
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.114628

High serum urate levels are the major risk factor for gout. URAT1, the primary transporter for urate absorption in the kidneys, is well known as an anti-hyperuricemia drug target. However, the clinical application of URAT1-targeted drugs is limited because of their low specificity and severe side effects. The lack of structural information impedes elucidation of the transport mechanism and the development of new drugs. Here, we present the cryoelectron microscopy (cryo-EM) structures of human URAT1(R477S), its complex with urate, and its closely related homolog OAT4. URAT1(R477S) and OAT4 exhibit major facilitator superfamily (MFS) folds with outward- and inward-open conformations, respectively. Structural comparison reveals a 30° rotation between the N-terminal and C-terminal domains, supporting an alternating access mechanism. A conserved arginine (OAT4-Arg473/URAT1-Arg477) is found to be essential for chloride-mediated inhibition. The URAT1(R477S)-urate complex reveals the specificity of urate recognition. Taken together, our study promotes our understanding of the transport mechanism and substrate selection of URAT1.
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•The human OAT4 structure is determined at 3.1 Å with an inward-open state•URAT1 structure is determined with R477S mutation in an outward-open state•A conserved arginine is found to be essential for chloride-mediated inhibition•URAT1(R477S)-urate structure suggests the recognition mode of urate in URAT1
URAT1 is involved in urate absorption and acts as a clinical anti-hyperuricemia target. He et al. determine the structures of human URAT1 with a disease mutation, its complex with urate, and the closely related homolog OAT4. The structural and biochemical characterizations provide a molecular basis for chloride inhibition and urate recognition.