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- EMDB-44080: Human urate transporter 1 URAT1 in complex with verinurad -

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Basic information

Entry
Database: EMDB / ID: EMD-44080
TitleHuman urate transporter 1 URAT1 in complex with verinurad
Map data
Sample
  • Complex: Human urate transporter 1 in complex with verinurad
    • Protein or peptide: Solute carrier family 22 member 12
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: verinurad
KeywordsSLC transporter / SLC22 family / inhibitor / uric acid / inward facing / MEMBRANE PROTEIN
Function / homology
Function and homology information


Defective SLC22A12 causes renal hypouricemia 1 (RHUC1) / Organic anion transport / urate transport / renal urate salt excretion / 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 / urate transport / renal urate salt excretion / 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 / response to xenobiotic stimulus / apical plasma membrane / 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: 3.7 Å
AuthorsDai Y / Lee CH
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM143282 United States
CitationJournal: Cell Res / Year: 2024
Title: Transport mechanism and structural pharmacology of human urate transporter URAT1.
Authors: Yaxin Dai / Chia-Hsueh Lee /
Abstract: Urate is an endogenous product of purine metabolism in the liver. High urate levels in the blood lead to gout, a very common and painful inflammatory arthritis. Excreted urate is reabsorbed in the ...Urate is an endogenous product of purine metabolism in the liver. High urate levels in the blood lead to gout, a very common and painful inflammatory arthritis. Excreted urate is reabsorbed in the kidney mainly by URAT1 antiporter, a key target for anti-gout drugs. To uncover the mechanisms of urate transport and drug inhibition, we determined cryo-EM structures of human URAT1 with urate, counter anion pyrazinoate, or anti-gout drugs of different chemotypes - lesinurad, verinurad, and dotinurad. We captured the outward-to-inward transition of URAT1 during urate uptake, revealing that urate binds in a phenylalanine-rich pocket and engages with key gating residues to drive the transport cycle. In contrast to the single binding site for urate, pyrazinoate interacts with three distinct, functionally relevant sites within URAT1, a mechanism that has not yet been observed in other anion antiporters. In addition, we found that while all three drugs compete with substrates and halt the transport cycle, verinurad and dotinurad further hijack gating residues to achieve high potency. These insights advance our understanding of organic anion transport and provide a foundation for designing improved gout therapeutics.
History
DepositionMar 13, 2024-
Header (metadata) releaseSep 18, 2024-
Map releaseSep 18, 2024-
UpdateSep 18, 2024-
Current statusSep 18, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_44080.png

Downloads & links

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Map

FileDownload / File: emd_44080.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.65 Å/pix.
x 384 pix.
= 249.216 Å		0.65 Å/pix.
x 384 pix.
= 249.216 Å		0.65 Å/pix.
x 384 pix.
= 249.216 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.649 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.158
Minimum - Maximum-0.68088275 - 0.98028916
Average (Standard dev.)0.0006507995 (±0.016542934)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 249.216 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_44080_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_44080_half_map_2.map
Projections & Slices
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Histogram

Histogram (log scale)

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Sample components

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Entire : Human urate transporter 1 in complex with verinurad

EntireName: Human urate transporter 1 in complex with verinurad
Components
  • Complex: Human urate transporter 1 in complex with verinurad
    • Protein or peptide: Solute carrier family 22 member 12
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: verinurad

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Supramolecule #1: Human urate transporter 1 in complex with verinurad

SupramoleculeName: Human urate transporter 1 in complex with verinurad / 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: 59.257402 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: FSELLDLVGG LGRFQVLQTM ALMVSIMWLC TQSMLENFSA AVPSHRCWAP LLDNSTAVST SLSPEALLAI SIPPGPNQRP HQCRRFRQP QWQLLDPNAT ATSWSEADTE PCVDGWVYDR SIFTSTIVAK WNLVCDSHAL KPMAQSIYLA GILVGAAACG P ASDRFGRR ...String:
FSELLDLVGG LGRFQVLQTM ALMVSIMWLC TQSMLENFSA AVPSHRCWAP LLDNSTAVST SLSPEALLAI SIPPGPNQRP HQCRRFRQP QWQLLDPNAT ATSWSEADTE PCVDGWVYDR SIFTSTIVAK WNLVCDSHAL KPMAQSIYLA GILVGAAACG P ASDRFGRR LVLTWSYLQM AVMGTAAAFA PAFPVYCLFR FLLAFAVAGV MMNTGTLLME WTAARARPLV MTLNSLGFSF GH GLTAAVA YGVRDWTLLQ LVVSVPFFLC FLYSWWLPES ARWLIIKGKP DQALQELRKV ARINGHKEAK NLTIEVLMSS VKE EVASAK EPRSVLDLFC VPGLRFRTCI STLCWFAFGF TFFGLALDLQ ALGSNIFLLQ MFIGVVDIPA KMGALLLLSH LGRR PTLAA SLLLAGLCIL ANTLVPHEMG ALRSALAVLG LGGVGAAFTC ITIYSSELFP TVLRMTAVGL GQMAARGGAI LGPLV RLLG VHGPWLPLLV YGTVPVLSGL AALLLPETQS LPLPDTIQDV QNQAVKKATH GTLGNSVLKS TQF

UniProtKB: Solute carrier family 22 member 12

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Macromolecule #2: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 2 / Number of copies: 1 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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Macromolecule #3: verinurad

MacromoleculeName: verinurad / type: ligand / ID: 3 / 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: 6.5
GridModel: Quantifoil R1.2/1.3 / Pretreatment - Type: PLASMA CLEANING
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: 77.0 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

Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 220155
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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