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- EMDB-37589: Cryo-EM structure of URAT1(R477S)-Urate complex -

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Basic information

Entry
Database: EMDB / ID: EMD-37589
TitleCryo-EM structure of URAT1(R477S)-Urate complex
Map data
Sample
  • Complex: Cryo-EM structure of URAT1(R477S)-Urate complex
    • Protein or peptide: Solute carrier family 22 member 12
  • Ligand: URIC ACID
KeywordsSLC / 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: 3.8 Å
AuthorsQian HW / He JJ
Funding support1 items
OrganizationGrant numberCountry
Other privateKY9100000034
CitationJournal: Cell Rep / Year: 2024
Title: Structural basis for the transport and substrate selection of human urate transporter 1.
Authors: Jingjing He / Guoyun Liu / Fang Kong / Qiulong Tan / Zhenzhou Wang / Meng Yang / Yonglin He / Xiaoxiao Jia / Chuangye Yan / Chao Wang / Hongwu Qian /
Abstract: High serum urate levels are the major risk factor for gout. URAT1, the primary transporter for urate absorption in the kidneys, is well known as an anti-hyperuricemia drug target. However, the ...High serum urate levels are the major risk factor for gout. URAT1, the primary transporter for urate absorption in the kidneys, is well known as an anti-hyperuricemia drug target. However, the clinical application of URAT1-targeted drugs is limited because of their low specificity and severe side effects. The lack of structural information impedes elucidation of the transport mechanism and the development of new drugs. Here, we present the cryoelectron microscopy (cryo-EM) structures of human URAT1(R477S), its complex with urate, and its closely related homolog OAT4. URAT1(R477S) and OAT4 exhibit major facilitator superfamily (MFS) folds with outward- and inward-open conformations, respectively. Structural comparison reveals a 30° rotation between the N-terminal and C-terminal domains, supporting an alternating access mechanism. A conserved arginine (OAT4-Arg473/URAT1-Arg477) is found to be essential for chloride-mediated inhibition. The URAT1(R477S)-urate complex reveals the specificity of urate recognition. Taken together, our study promotes our understanding of the transport mechanism and substrate selection of URAT1.
History
DepositionSep 26, 2023-
Header (metadata) releaseAug 28, 2024-
Map releaseAug 28, 2024-
UpdateNov 6, 2024-
Current statusNov 6, 2024Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_37589.png

Downloads & links

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Map

FileDownload / File: emd_37589.map.gz / Format: CCP4 / Size: 22.2 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.07 Å/pix.
x 180 pix.
= 192.6 Å		1.07 Å/pix.
x 180 pix.
= 192.6 Å		1.07 Å/pix.
x 180 pix.
= 192.6 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.07 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.116
Minimum - Maximum-2.1233597 - 2.7073374
Average (Standard dev.)0.0018584916 (±0.06003855)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions180180180
Spacing180180180
CellA=B=C: 192.6 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_37589_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_37589_half_map_2.map
Projections & Slices
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Sample components

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Entire : Cryo-EM structure of URAT1(R477S)-Urate complex

EntireName: Cryo-EM structure of URAT1(R477S)-Urate complex
Components
  • Complex: Cryo-EM structure of URAT1(R477S)-Urate complex
    • Protein or peptide: Solute carrier family 22 member 12
  • Ligand: URIC ACID

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Supramolecule #1: Cryo-EM structure of URAT1(R477S)-Urate complex

SupramoleculeName: Cryo-EM structure of URAT1(R477S)-Urate complex / 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: 58.027961 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 ASGGA ILGP LVRLLGVHGP WLPLLVYGTV PVLSGLAALL LPETQSLPLP DTIQDVQNQA VKKA

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: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.7 µm / Nominal defocus min: 1.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 392817
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION

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