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- EMDB-61155: Cryo-EM Structure of URAT1 in Complex with Benzbromarone -

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Basic information

Entry
Database: EMDB / ID: EMD-61155
TitleCryo-EM Structure of URAT1 in Complex with Benzbromarone
Map data
Sample
  • Complex: Cryo-EM Structure of URAT1 in Complex with Benzbromarone
    • Protein or peptide: Solute carrier family 22 member 12
  • Ligand: [3,5-bis(bromanyl)-4-oxidanyl-phenyl]-(2-ethyl-1-benzofuran-3-yl)methanone
KeywordsInhibitor / complex / MEMBRANE PROTEIN
Function / homology
Function and homology information


Organic anion transport / 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 / 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: 3.2 Å
AuthorsFan J / Lei X
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: JACS Au / Year: 2025
Title: Structural Basis for Inhibition of Urate Reabsorption in URAT1.
Authors: Junping Fan / Wenjun Xie / Han Ke / Jing Zhang / Jin Wang / Haijun Wang / Nianxin Guo / Yingjie Bai / Xiaoguang Lei /
Abstract: The urate transporter 1 (URAT1) is the primary urate transporter in the kidney responsible for urate reabsorption and, therefore, is crucial for urate homeostasis. Hyperuricemia causes the common ...The urate transporter 1 (URAT1) is the primary urate transporter in the kidney responsible for urate reabsorption and, therefore, is crucial for urate homeostasis. Hyperuricemia causes the common human disease gout and other pathological consequences. Inhibition of urate reabsorption through URAT1 has been shown as a promising strategy in alleviating hyperuricemia, and clinical and preclinical drug candidates targeting URAT1 are emerging. However, how small molecules inhibit URAT1 remains undefined, and the lack of accurate URAT1 complex structures hinders the development of better therapeutics. Here, we present cryoelectron microscopy structures of a humanized rat URAT1 bound with benzbromarone, lingdolinurad, and verinurad, elucidating the structural basis for drug recognition and inhibition. The three small molecules reside in the URAT1 central cavity with different binding modes, locking URAT1 in an inward-facing conformation. This study provides mechanistic insights into the drug modulation of URAT1 and sheds light on the rational design of potential URAT1-specific therapeutics for treating hyperuricemia.
History
DepositionAug 13, 2024-
Header (metadata) releaseFeb 26, 2025-
Map releaseFeb 26, 2025-
UpdateJun 18, 2025-
Current statusJun 18, 2025Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_61155.png

Downloads & links

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Map

FileDownload / File: emd_61155.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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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: 0.18
Minimum - Maximum-0.94150305 - 1.3878593
Average (Standard dev.)0.00039445545 (±0.032036383)
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: #1

Fileemd_61155_half_map_1.map
Projections & Slices
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Density Histograms

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Half map: #2

Fileemd_61155_half_map_2.map
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Sample components

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Entire : Cryo-EM Structure of URAT1 in Complex with Benzbromarone

EntireName: Cryo-EM Structure of URAT1 in Complex with Benzbromarone
Components
  • Complex: Cryo-EM Structure of URAT1 in Complex with Benzbromarone
    • Protein or peptide: Solute carrier family 22 member 12
  • Ligand: [3,5-bis(bromanyl)-4-oxidanyl-phenyl]-(2-ethyl-1-benzofuran-3-yl)methanone

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Supramolecule #1: Cryo-EM Structure of URAT1 in Complex with Benzbromarone

SupramoleculeName: Cryo-EM Structure of URAT1 in Complex with Benzbromarone
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: 60.233234 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 ILGP LVRLLGVYGS WLPLLVYGVV PVLSGLAALL LPETKNLPLP DTIQDIQKQS VKKVTHDIAG GSVLKSARL

UniProtKB: Solute carrier family 22 member 12

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Macromolecule #2: [3,5-bis(bromanyl)-4-oxidanyl-phenyl]-(2-ethyl-1-benzofuran-3-yl)...

MacromoleculeName: [3,5-bis(bromanyl)-4-oxidanyl-phenyl]-(2-ethyl-1-benzofuran-3-yl)methanone
type: ligand / ID: 2 / Number of copies: 1 / Formula: R75
Molecular weightTheoretical: 424.083 Da
Chemical component information

ChemComp-R75:
[3,5-bis(bromanyl)-4-oxidanyl-phenyl]-(2-ethyl-1-benzofuran-3-yl)methanone / antiarrhythmic, inhibitor*YM

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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: FLOOD BEAM / 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 AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER / Details: AF2 model
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 69925
Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: MAXIMUM LIKELIHOOD

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