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- EMDB-61194: Cryo-EM structure of URAT1 in complex with verinurad -

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Basic information

Entry
Database: EMDB / ID: EMD-61194
TitleCryo-EM structure of URAT1 in complex with verinurad
Map data
Sample
  • Complex: structure of URAT1
    • Protein or peptide: Solute carrier family 22 member 12
  • Ligand: verinurad
Keywordsprotein structure / STRUCTURAL PROTEIN / TRANSPORT PROTEIN
Function / homology
Function and homology information


Organic anion transport by SLC22 transporters / renal urate salt excretion / urate transport / urate metabolic process / urate transmembrane transporter activity / organic anion transport / monoatomic ion transport / PDZ domain binding / brush border membrane / cellular response to insulin stimulus ...Organic anion transport by SLC22 transporters / renal urate salt excretion / urate transport / urate metabolic process / urate transmembrane transporter activity / organic anion transport / monoatomic ion transport / PDZ domain binding / brush border membrane / cellular response to insulin stimulus / apical plasma membrane / response to xenobiotic stimulus / membrane / plasma membrane
Similarity search - Function
Major facilitator, sugar transporter-like / Sugar (and other) transporter / Major facilitator superfamily domain / Major facilitator superfamily (MFS) profile. / MFS transporter superfamily
Similarity search - Domain/homology
Solute carrier family 22 member 12
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsZhao Y / Yu Z
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Nat Commun / Year: 2025
Title: Molecular mechanism of drug inhibition of URAT1.
Authors: Zhuoya Yu / Tuo Hu / Jiawei Su / Jun Zhao / Renjie Li / Qiao Ma / Qihao Chen / Qinru Bai / Yanli Dong / Pu Yuan / Na Li / Xuejun Cai Zhang / Yan Zhao /
Abstract: Hyperuricemia, characterized by elevated serum urate levels, is a key factor in the pathogenesis of gout. URAT1 is essential for renal urate reabsorption and has emerged as a critical therapeutic ...Hyperuricemia, characterized by elevated serum urate levels, is a key factor in the pathogenesis of gout. URAT1 is essential for renal urate reabsorption and has emerged as a critical therapeutic target for managing hyperuricemia. However, the precise transport mechanism and the inhibitory effects of uricosuric drugs on URAT1 remain unclear. Here, we present structures of the double-mutant rat homolog of URAT1 in complex with its substrate urate, and the clinical drugs benzbromarone, lesinurad, verinurad, and sulfinpyrazone. The urate-bound structure elucidates key residues involved in recognizing urate, while the structures bound with drugs clearly demonstrate the distinct binding mode of each drug with URAT1. These drugs stabilize URAT1's inward-facing state, blocking conformational transitions. Additionally, critical interactions essential for its conformational transition are identified. These findings provide a molecular framework for understanding the physiological function of URAT1 and for developing more efficacious therapies to treat hyperuricemia.
History
DepositionAug 18, 2024-
Header (metadata) releaseAug 13, 2025-
Map releaseAug 13, 2025-
UpdateAug 13, 2025-
Current statusAug 13, 2025Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_61194.png

Downloads & links

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Map

FileDownload / File: emd_61194.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

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AxesZ (Sec.)Y (Row.)X (Col.)
0.85 Å/pix.
x 256 pix.
= 217.6 Å		0.85 Å/pix.
x 256 pix.
= 217.6 Å		0.85 Å/pix.
x 256 pix.
= 217.6 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.85 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.191
Minimum - Maximum-1.2598299 - 1.8431025
Average (Standard dev.)0.00036971632 (±0.03396326)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 217.6 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_61194_half_map_1.map
Projections & Slices
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Histogram (log scale)

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Half map: #1

Fileemd_61194_half_map_2.map
Projections & Slices
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Sample components

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Entire : structure of URAT1

EntireName: structure of URAT1
Components
  • Complex: structure of URAT1
    • Protein or peptide: Solute carrier family 22 member 12
  • Ligand: verinurad

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Supramolecule #1: structure of URAT1

SupramoleculeName: structure of URAT1 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Rattus norvegicus (Norway rat)

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Macromolecule #1: Solute carrier family 22 member 12

MacromoleculeName: Solute carrier family 22 member 12 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Rattus norvegicus (Norway rat)
Molecular weightTheoretical: 60.251273 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MAFPELLDRV GGRGRFQLLQ AVALVTPILW VTTQSMLENF SAAVPHHRCW VPLLDNSTSQ ASIPGDFGRD VLLAVSIPPG PDQRPHQCL RFRQPQWQLI ESNTTATNWS DADTEPCEDG WVYDHSTFRS TIVTTWDLVC DSQALRPMAQ SIFLAGILVG A AVCGHASD ...String:
MAFPELLDRV GGRGRFQLLQ AVALVTPILW VTTQSMLENF SAAVPHHRCW VPLLDNSTSQ ASIPGDFGRD VLLAVSIPPG PDQRPHQCL RFRQPQWQLI ESNTTATNWS DADTEPCEDG WVYDHSTFRS TIVTTWDLVC DSQALRPMAQ SIFLAGILVG A AVCGHASD RFGRRRVLTW SYLLVSVSGT IAALMPTFPL YCLFRFLVAS AVAGVMMNTA SLLMEWTSAQ AGPLMMTLNA LG FSFGQVL TGSVAYGVRS WRMLQLAVSA PFFLFFVYSW WLPESARWLI TVGRLDQSLR ELQRVAAVNR RKAEADTLTV EVL RSAMQE EPNGNQAGAR LGTLLHTPGL RLRTFISMLC WFAFGFTFFG LALDLQALGS NIFLLQALIG IVDLPVKMGS LLLL SRLGR RLCQASSLVL PGLCILANIL VPREMGILRS SLAVLGLGSL GAAFTCVTIF SSELFPTVIR MTAVGLGQVA ARGGA MLGP LVRLLGVYGS WLPLLVYGVV PVLSGLAALL LPETKNLPLP DTIQDIQKQS VKKVTHDIAG GSVLKSARL

UniProtKB: Solute carrier family 22 member 12

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Macromolecule #2: verinurad

MacromoleculeName: verinurad / type: ligand / ID: 2 / Number of copies: 1 / Formula: A1AIJ
Molecular weightTheoretical: 348.418 Da

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING ONLY
Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 96361
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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