[English] 日本語
Yorodumi
- EMDB-46950: Structure of URAT1 in complex with lesinurad -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: EMDB / ID: EMD-46950
TitleStructure of URAT1 in complex with lesinurad
Map datahalf map 1
Sample
  • Complex: URAT1
    • Protein or peptide: URAT1
  • Ligand: lesinurad
KeywordsMembrane protein / membrane transporter / TRANSPORT PROTEIN
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.74 Å
AuthorsSuo Y / Fedor JG / Lee S-Y
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI) United States
CitationJournal: Nat Commun / Year: 2025
Title: Molecular basis of the urate transporter URAT1 inhibition by gout drugs.
Authors: Yang Suo / Justin G Fedor / Han Zhang / Kalina Tsolova / Xiaoyu Shi / Kedar Sharma / Shweta Kumari / Mario Borgnia / Peng Zhan / Wonpil Im / Seok-Yong Lee /
Abstract: Hyperuricemia is a condition when uric acid, a waste product of purine metabolism, accumulates in the blood. Untreated hyperuricemia can lead to crystal formation of monosodium urate in the joints, ...Hyperuricemia is a condition when uric acid, a waste product of purine metabolism, accumulates in the blood. Untreated hyperuricemia can lead to crystal formation of monosodium urate in the joints, causing a painful inflammatory disease known as gout. These conditions are associated with many other diseases and affect a significant and increasing proportion of the population. The human urate transporter 1 (URAT1) is responsible for the reabsorption of ~90% of uric acid in the kidneys back into the blood, making it a primary target for treating hyperuricemia and gout. Despite decades of research and development, clinically available URAT1 inhibitors have limitations because the molecular basis of URAT1 inhibition by gout drugs remains unknown. Here we present cryo-electron microscopy structures of URAT1 alone and in complex with three clinically relevant inhibitors: benzbromarone, lesinurad, and the recently developed compound TD-3. Together with functional experiments and molecular dynamics simulations, we reveal that these inhibitors bind selectively to URAT1 in inward-open states. Furthermore, we discover differences in the inhibitor-dependent URAT1 conformations as well as interaction networks, which contribute to drug specificity. Our findings illuminate a general theme for URAT1 inhibition, paving the way for the design of next-generation URAT1 inhibitors in the treatment of gout and hyperuricemia.
History
DepositionSep 8, 2024-
Header (metadata) releaseJun 18, 2025-
Map releaseJun 18, 2025-
UpdateJun 18, 2025-
Current statusJun 18, 2025Processing site: RCSB / Status: Released

-
Structure visualization

Supplemental images

emd_46950.png

Downloads & links

-
Map

FileDownload / File: emd_46950.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationhalf map 1
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 256 pix.
= 211.354 Å		0.83 Å/pix.
x 256 pix.
= 211.354 Å		0.83 Å/pix.
x 256 pix.
= 211.354 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.8256 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.25
Minimum - Maximum-1.183307 - 1.6596426
Average (Standard dev.)0.0020180633 (±0.077320784)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 211.3536 Å
α=β=γ: 90.0 °

-
Supplemental data

-
Half map: half map 1

Fileemd_46950_half_map_1.map
Annotationhalf map 1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

-
Half map: half map 2

Fileemd_46950_half_map_2.map
Annotationhalf map 2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

-
Sample components

-
Entire : URAT1

EntireName: URAT1
Components
  • Complex: URAT1
    • Protein or peptide: URAT1
  • Ligand: lesinurad

-
Supramolecule #1: URAT1

SupramoleculeName: URAT1 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 55 KDa

-
Macromolecule #1: URAT1

MacromoleculeName: URAT1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 55.379844 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MAFSELLDQV GGLGRFQVLQ TVALVVPIMW LCTQSMLENF SAAVPSHRCW VPLLDNSTAQ ASVPGALGPE ALLAVSIPPG PNQGPHQCR RFRQPQWQLL DPNATATNWS EAATEPCVDG WVYDRSTFTS TIVAKWDLVC DSQALKPMAQ SIYLAGILVG A AVCGPASD ...String:
MAFSELLDQV GGLGRFQVLQ TVALVVPIMW LCTQSMLENF SAAVPSHRCW VPLLDNSTAQ ASVPGALGPE ALLAVSIPPG PNQGPHQCR RFRQPQWQLL DPNATATNWS EAATEPCVDG WVYDRSTFTS TIVAKWDLVC DSQALKPMAQ SIYLAGILVG A AVCGPASD RFGRRLVLTW SYLQMAVSGT AAAFAPTFPV YCLFRFLVAF AVAGVMMNTG TLVMEWTSAQ ARPLVMTLNS LG FSFGHVL MAAVAYGVRD WALLQLVVSV PFFLCFVYSC WLAESARWLL ITGRLDRGLR ELQRVAAING KRAVGDTLTP QVL LSAMQE ELSVGQAPAS LGTLLRTPGL RLRTCISTLC WFAFGFTFFG LALDLQALGS NIFLLQVLIG VVDIPAKIGT LLLL SRLGR RPTQAASLVL AGLCILANTL VPHEMGALRS ALAVLGLGGL GAAFTCITIY SGELFPTVLR MTAVGLGQMA ARGGA ILGP LVRLLGVHGP WLPLLVYGTV PVLSGLAALL LPET

-
Macromolecule #2: lesinurad

MacromoleculeName: lesinurad / type: ligand / ID: 2 / Number of copies: 1 / Formula: A1AIL
Molecular weightTheoretical: 404.281 Da

-
Experimental details

-
Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

-
Sample preparation

Concentration10 mg/mL
BufferpH: 8
Component:
ConcentrationFormulaName
20.0 mMTrisTris
150.0 mMNaClNaCl
0.005 %LMNGLMNG
GridModel: Quantifoil R1.2/1.3 / Support film - Material: GOLD / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 300 sec. / Pretreatment - Atmosphere: AIR / Pretreatment - Pressure: 0.00039000000000000005 kPa
VitrificationCryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 280 K / Instrument: LEICA EM GP
DetailsMonodisperse sample

-
Electron microscopy

MicroscopeTFS KRIOS
TemperatureMax: 70.0 K
Specialist opticsEnergy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Digitization - Dimensions - Width: 5760 pixel / Digitization - Dimensions - Height: 4092 pixel / Number grids imaged: 1 / Number real images: 18880 / Average exposure time: 1.8 sec. / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 100.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.0 µm / Nominal magnification: 105000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

+
Image processing

Particle selectionNumber selected: 9515658
CTF correctionSoftware - Name: cryoSPARC (ver. 4.0) / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionNumber classes used: 1 / Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 2.74 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.0) / Number images used: 512313
Initial angle assignmentType: ANGULAR RECONSTITUTION / Software - Name: cryoSPARC (ver. 4.0)
Final angle assignmentType: ANGULAR RECONSTITUTION / Software - Name: cryoSPARC (ver. 4.0)

-
Atomic model buiding 1

Initial modelPDB ID:

8et6


Chain - Chain ID: A / Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementSpace: REAL / Protocol: FLEXIBLE FIT / Overall B value: 200
Output model

PDB-9dkb:
Structure of URAT1 in complex with lesinurad

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more