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- EMDB-61404: Human URAT1 bound to dotinurad -

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Basic information

Entry
Database: EMDB / ID: EMD-61404
TitleHuman URAT1 bound to dotinurad
Map data
Sample
  • Complex: human uric acid transporter 1 with dotinurad
    • Protein or peptide: Solute carrier family 22 member 12
  • Ligand: dotinurad
KeywordsURAT1 / TRANSPORT PROTEIN
Function / homology
Function and homology information


Defective SLC22A12 causes renal hypouricemia 1 (RHUC1) / Organic anion transport / renal urate salt excretion / urate transport / urate metabolic process / urate transmembrane transporter activity / organic anion transport / cellular homeostasis / monoatomic ion transport / PDZ domain binding ...Defective SLC22A12 causes renal hypouricemia 1 (RHUC1) / Organic anion transport / renal urate salt excretion / urate transport / urate metabolic process / urate transmembrane transporter activity / organic anion transport / cellular homeostasis / monoatomic ion transport / PDZ domain binding / brush border membrane / cellular response to insulin stimulus / apical plasma membrane / response to xenobiotic stimulus / extracellular exosome / membrane / plasma membrane
Similarity search - Function
Major facilitator superfamily / Major Facilitator Superfamily / 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 speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.6 Å
AuthorsWu C / Xu HE
Funding support China, 2 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32130022 China
National Natural Science Foundation of China (NSFC)32301016 China
Citation
Journal: Cell Discov / Year: 2025
Title: Molecular mechanisms of urate transport by the native human URAT1 and its inhibition by anti-gout drugs.
Authors: Canrong Wu / Chao Zhang / Sanshan Jin / James Jiqi Wang / Antao Dai / Jiuyin Xu / Heng Zhang / Xuemei Yang / Xinheng He / Qingning Yuan / Wen Hu / Youwei Xu / Mingwei Wang / Yi Jiang / Dehua Yang / H Eric Xu /
Abstract: Gout, a common and painful disease, stems from hyperuricemia, where elevated blood urate levels lead to urate crystal formation in joints and kidneys. The human urate transporter 1 (hURAT1) plays a ...Gout, a common and painful disease, stems from hyperuricemia, where elevated blood urate levels lead to urate crystal formation in joints and kidneys. The human urate transporter 1 (hURAT1) plays a critical role in urate homeostasis by facilitating urate reabsorption in the renal proximal tubule, making it a key target for gout therapy. Pharmacological inhibition of hURAT1 with drugs such as dotinurad, benzbromarone, lesinurad, and verinurad promotes urate excretion and alleviates gout symptoms. Here, we present cryo-electron microscopy structures of native hURAT1 bound with these anti-gout drugs in the inward-open state, and with urate in inward-open, outward-open, and occluded states. Complemented by mutagenesis and cell-based assays, these structures reveal the mechanisms of urate reabsorption and hURAT1 inhibition. Our findings elucidate the molecular basis of urate transport and anti-gout medication action and provide a structural framework for the rational design of next-generation therapies for hyperuricemia and gout.
#1: Journal: Biorxiv / Year: 2024
Title: Molecular mechanisms of uric acid transport by the native human URAT1 and its inhibition by anti-gout drugs
Authors: Wu C / Zhang C / Jin S / Wang JJ / Dai A / Xu J / Zhang H / Yang X / He X / Yuan Q / Hu W / Xu Y / Wang M / Jiang Y / Yang D / Xu HE
History
DepositionSep 1, 2024-
Header (metadata) releaseOct 16, 2024-
Map releaseOct 16, 2024-
UpdateApr 16, 2025-
Current statusApr 16, 2025Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_61404.png

Downloads & links

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Map

FileDownload / File: emd_61404.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.73 Å/pix.
x 256 pix.
= 186.88 Å		0.73 Å/pix.
x 256 pix.
= 186.88 Å		0.73 Å/pix.
x 256 pix.
= 186.88 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.73 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.3
Minimum - Maximum-2.9408302 - 3.3917308
Average (Standard dev.)0.0027691638 (±0.08239064)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 186.88 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_61404_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_61404_half_map_2.map
Projections & Slices
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Histogram

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Sample components

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Entire : human uric acid transporter 1 with dotinurad

EntireName: human uric acid transporter 1 with dotinurad
Components
  • Complex: human uric acid transporter 1 with dotinurad
    • Protein or peptide: Solute carrier family 22 member 12
  • Ligand: dotinurad

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Supramolecule #1: human uric acid transporter 1 with dotinurad

SupramoleculeName: human uric acid transporter 1 with dotinurad / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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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: Homo sapiens (human)
Molecular weightTheoretical: 59.671828 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MAFSELLDLV GGLGRFQVLQ TMALMVSIMW LCTQSMLENF SAAVPSHRCW APLLDNSTAQ ASILGSLSPE ALLAISIPPG PNQRPHQCR RFRQPQWQLL DPNATATSWS EADTEPCVDG WVYDRSIFTS TIVAKWNLVC DSHALKPMAQ SIYLAGILVG A AACGPASD ...String:
MAFSELLDLV GGLGRFQVLQ TMALMVSIMW LCTQSMLENF SAAVPSHRCW APLLDNSTAQ ASILGSLSPE ALLAISIPPG PNQRPHQCR RFRQPQWQLL DPNATATSWS EADTEPCVDG WVYDRSIFTS TIVAKWNLVC DSHALKPMAQ SIYLAGILVG A AACGPASD RFGRRLVLTW SYLQMAVMGT AAAFAPAFPV YCLFRFLLAF AVAGVMMNTG TLLMEWTAAR ARPLVMTLNS LG FSFGHGL TAAVAYGVRD WTLLQLVVSV PFFLCFLYSW WLAESARWLL TTGRLDWGLQ ELWRVAAING KGAVQDTLTP EVL LSAMRE ELSMGQPPAS LGTLLRMPGL RFRTCISTLC WFAFGFTFFG LALDLQALGS NIFLLQMFIG VVDIPAKMGA LLLL SHLGR RPTLAASLLL AGLCILANTL VPHEMGALRS ALAVLGLGGV GAAFTCITIY SSELFPTVLR MTAVGLGQMA ARGGA ILGP LVRLLGVHGP WLPLLVYGTV PVLSGLAALL LPETQSLPLP DTIQDVQNQA VKKATHGTLG NSVLKSTQF

UniProtKB: Solute carrier family 22 member 12

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Macromolecule #2: dotinurad

MacromoleculeName: dotinurad / type: ligand / ID: 2 / Number of copies: 1 / Formula: A1AIK
Molecular weightTheoretical: 358.197 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 TALOS ARCTICA
Image recordingFilm or detector model: FEI FALCON I (4k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELD / Nominal defocus max: 5.0 µm / Nominal defocus min: 1.2 µm
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 64698
Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: ANGULAR RECONSTITUTION
FSC plot (resolution estimation)

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