8WJQ

Cryo-EM structure of URAT1(R477S)-Urate complex

Summary for 8WJQ

• Entry DOI: 10.2210/pdb8wjq/pdb
• EMDB information: 37589
• Descriptor: Solute carrier family 22 member 12, URIC ACID (2 entities in total)
• Functional Keywords: slc, transport protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 58196.07

Authors

Qian, H.W.,He, J.J. (deposition date: 2023-09-26, release date: 2024-08-28, Last modification date: 2025-07-23)

Primary citation

He, J.,Liu, G.,Kong, F.,Tan, Q.,Wang, Z.,Yang, M.,He, Y.,Jia, X.,Yan, C.,Wang, C.,Qian, H.
Structural basis for the transport and substrate selection of human urate transporter 1.
Cell Rep, 43:114628-114628, 2024

PubMed Abstract: 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.

PubMed: 39146184
DOI: 10.1016/j.celrep.2024.114628

Experimental method

ELECTRON MICROSCOPY (3.8 Å)