Database of articles cited by EMDB/PDB/SASBDB data

Keywords
Structure methods	All X-ray diffraction NMR electron microscopy small angle scattering neutron diffraction fiber diffraction powder diffraction infrared spectroscopy EPR fluorescence transfer theoretical model Hybrid
Author
Journal
IF	>30 >20 >10 >5 all

Title	Transport mechanism and structural pharmacology of human urate transporter URAT1.
Journal, issue, pages	Cell Res, Vol. 34, Issue 11, Page 776-787, Year 2024
Publish date	Sep 9, 2024
Authors	Yaxin Dai / Chia-Hsueh Lee /
PubMed 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 ...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.
External links	Cell Res / PubMed:39245778 / PubMed Central
Methods	EM (single particle)
Resolution	2.7 - 3.7 Å
Structure data	44077 9b1f EMDB-44077, PDB-9b1f: Human urate transporter 1 URAT1 in apo state Method: EM (single particle) / Resolution: 2.9 Å 44078 9b1g EMDB-44078, PDB-9b1g: Human urate transporter 1 URAT1 in complex with dotinurad Method: EM (single particle) / Resolution: 2.7 Å 44079 9b1h EMDB-44079, PDB-9b1h: Human urate transporter 1 URAT1 in complex with lesinurad Method: EM (single particle) / Resolution: 2.9 Å 44080 9b1i EMDB-44080, PDB-9b1i: Human urate transporter 1 URAT1 in complex with verinurad Method: EM (single particle) / Resolution: 3.7 Å 44081 9b1j EMDB-44081, PDB-9b1j: Urate bound human URAT1 in the inward-facing state Method: EM (single particle) / Resolution: 3.0 Å 44082 9b1k EMDB-44082, PDB-9b1k: Urate bound human URAT1 in the occluded state Method: EM (single particle) / Resolution: 3.3 Å 44083 9b1l EMDB-44083, PDB-9b1l: Urate bound human URAT1 in the outward-facing state. Method: EM (single particle) / Resolution: 3.1 Å 44084 9b1m EMDB-44084, PDB-9b1m: Pyrazinoate bound human URAT1 in the inward-facing state (site1) Method: EM (single particle) / Resolution: 3.0 Å 44085 9b1n EMDB-44085, PDB-9b1n: Pyrazinoate bound human URAT1 in the inward-facing state (site2) Method: EM (single particle) / Resolution: 3.1 Å 44086 9b1o EMDB-44086, PDB-9b1o: Pyrazinoate bound human URAT1 in the inward-facing state (site3) Method: EM (single particle) / Resolution: 3.1 Å
Chemicals	ChemComp-NAG: 2-acetamido-2-deoxy-beta-D-glucopyranose PDB-1aik: HIV GP41 CORE STRUCTURE PDB-1ail: N-TERMINAL FRAGMENT OF NS1 PROTEIN FROM INFLUENZA A VIRUS PDB-1aij: PHOTOSYNTHETIC REACTION CENTER FROM RHODOBACTER SPHAEROIDES IN THE CHARGE-NEUTRAL DQAQB STATE ChemComp-URC: URIC ACID ChemComp-PO4: PHOSPHATE ION ChemComp-VGL: PYRAZINE-2-CARBOXYLIC ACID
Source	homo sapiens (human)
Keywords	MEMBRANE PROTEIN / SLC transporter / SLC22A family / uric acid / inward facing / SLC22 family / inward open / inhibitor / outward facing