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- EMDB-60823: Structure of human URAT1 bound with urate -

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Basic information

Entry
Database: EMDB / ID: EMD-60823
TitleStructure of human URAT1 bound with urate
Map datasharpened_map
Sample
  • Complex: human urate transporter 1
    • Protein or peptide: Solute carrier family 22 member 12
  • Ligand: URIC ACID
KeywordsSLC22 / urate / gout / benzbromarone / 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: 3.26 Å
AuthorsGuo WJ / Wei M / Chen L
Funding support China, 2 items
OrganizationGrant numberCountry
Ministry of Science and Technology (MoST, China)2022YFA0806504 China
National Natural Science Foundation of China (NSFC)32225027 China
CitationJournal: Nat Commun / Year: 2025
Title: Mechanisms of urate transport and uricosuric drugs inhibition in human URAT1.
Authors: Wenjun Guo / Miao Wei / Yunfeng Li / Jiaxuan Xu / Jiahe Zang / Yuezhou Chen / Lei Chen /
Abstract: High urate levels in circulation lead to the accumulation of urate crystals in joints and ultimately inflammation and gout. The reabsorption process of urate in the kidney by the urate transporter ...High urate levels in circulation lead to the accumulation of urate crystals in joints and ultimately inflammation and gout. The reabsorption process of urate in the kidney by the urate transporter URAT1 plays a pivotal role in controlling serum urate levels. Pharmacological inhibition of URAT1 by uricosuric drugs is a valid strategy for gout management. Despite the clinical significance of URAT1, its structural mechanism and dynamics remain incompletely understood. Here, we report the structures of human URAT1 (hURAT1) in complex with substrate urate or inhibitors benzbromarone and verinurad at resolution ranges from 3.0 to 3.3 Å. We observe urate in the central substrate-binding site of hURAT1 in the outward-facing conformation and urate is wrapped in the center of hURAT1 by five phenylalanines and coordinated by two positively charged residues on each side. Uricosuric compounds benzbromarone and verinurad occupy the urate-binding site of hURAT1 in the inward-facing conformation. Structural comparison between different conformations of hURAT1 reveals the rocker-switch-like mechanism for urate transport. Benzbromarone and verinurad exert their inhibitory effect by blocking not only the binding of urate but also the structural isomerization of hURAT1.
History
DepositionJul 16, 2024-
Header (metadata) releaseJan 15, 2025-
Map releaseJan 15, 2025-
UpdateMay 7, 2025-
Current statusMay 7, 2025Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_60823.png

Downloads & links

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Map

FileDownload / File: emd_60823.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationsharpened_map
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
1.07 Å/pix.
x 256 pix.
= 273.152 Å		1.07 Å/pix.
x 256 pix.
= 273.152 Å		1.07 Å/pix.
x 256 pix.
= 273.152 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.067 Å
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 1.38
Minimum - Maximum-4.872946 - 7.816533
Average (Standard dev.)-0.0007751279 (±0.12953438)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 273.152 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_60823_msk_1.map
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Additional map: unsharpened map

Fileemd_60823_additional_1.map
Annotationunsharpened_map
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Half map: half map A

Fileemd_60823_half_map_1.map
Annotationhalf_map_A
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Half map: half map B

Fileemd_60823_half_map_2.map
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Sample components

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Entire : human urate transporter 1

EntireName: human urate transporter 1
Components
  • Complex: human urate transporter 1
    • Protein or peptide: Solute carrier family 22 member 12
  • Ligand: URIC ACID

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Supramolecule #1: human urate transporter 1

SupramoleculeName: human urate transporter 1 / 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: 59.977066 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: GPEFMAFSEL LDLVGGLGRF QVLQTMALMV SIMWLCTQSM LENFSAAVPS HRCWAPLLDN STAQASILGS LSPEALLAIS IPPGPNQRP HQCRRFRQPQ WQLLDPNATA TSWSEADTEP CVDGWVYDRS IFTSTIVAKW NLVCDSHALK PMAQSIYLAG I LVGAAVCG ...String:
GPEFMAFSEL LDLVGGLGRF QVLQTMALMV SIMWLCTQSM LENFSAAVPS HRCWAPLLDN STAQASILGS LSPEALLAIS IPPGPNQRP HQCRRFRQPQ WQLLDPNATA TSWSEADTEP CVDGWVYDRS IFTSTIVAKW NLVCDSHALK PMAQSIYLAG I LVGAAVCG PASDRFGRRL VLTWSYLQMA VSGTAAAFAP TFPVYCLFRF LLAFAVAGVM MNTGTLLMEW TSARARPLVM TL NSLGFSF GHGLTAAVAY GVRDWTLLQL AVSVPFFLCF LYSWWLAESA RWLLTTGRLD RGLQELRRVA AINGKRAVQD TLT PEVLLS AMREELSVGQ APASLGTLLR TPGLRLRTCI STLCWFAFGF TFFGLALDLQ ALGSNIFLLQ VLIGVVDIPA KMGA LLLLS RLGRRPTLAA SLLLAGLCIL ANTLVPHEMG ALRSALAVLG LGGVGAAFTC ITIYSSELFP TVLRMTAVGL GQMAA RGGA ILGPLVRLLG VHGPWLPLLV YGTVPVLSGL AALLLPETQS LPLPDTIQDV QNQAVKKATH GTLGNSVLKS TQF

UniProtKB: Solute carrier family 22 member 12

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Macromolecule #2: URIC ACID

MacromoleculeName: URIC ACID / type: ligand / ID: 2 / Number of copies: 1 / Formula: URC
Molecular weightTheoretical: 168.11 Da
Chemical component information

ChemComp-URC:
URIC ACID

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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) / Number real images: 4381 / Average electron dose: 70.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.8 µm / Nominal defocus min: 1.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 6243714
CTF correctionType: NONE
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.26 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 310852
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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