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- EMDB-38966: Cryo-EM structure of human urate transporter GLUT9 bound to subst... -

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Basic information

Entry
Database: EMDB / ID: EMD-38966
TitleCryo-EM structure of human urate transporter GLUT9 bound to substrate urate
Map dataCryo-EM structure of human urate transporter GLUT9 bound to substrate urate in detergent micelles
Sample
  • Complex: GLUT9 in complex with urate
    • Protein or peptide: Solute carrier family 2, facilitated glucose transporter member 9
  • Ligand: URIC ACID
KeywordsGLUT9 / Urate / TRANSPORT PROTEIN
Function / homology
Function and homology information


Defective SLC2A9 causes hypouricemia renal 2 (RHUC2) / fructose transmembrane transporter activity / hexose transmembrane transporter activity / monosaccharide transmembrane transport / fructose transmembrane transport / hexose transmembrane transport / carbohydrate:proton symporter activity / Cellular hexose transport / glucose transmembrane transporter activity / urate transport ...Defective SLC2A9 causes hypouricemia renal 2 (RHUC2) / fructose transmembrane transporter activity / hexose transmembrane transporter activity / monosaccharide transmembrane transport / fructose transmembrane transport / hexose transmembrane transport / carbohydrate:proton symporter activity / Cellular hexose transport / glucose transmembrane transporter activity / urate transport / urate metabolic process / urate transmembrane transporter activity / glucose transmembrane transport / transmembrane transporter activity / basolateral plasma membrane / apical plasma membrane / membrane / plasma membrane
Similarity search - Function
Glucose transporter GLUT / Sugar/inositol transporter / Sugar transport proteins signature 2. / Sugar transport proteins signature 1. / Major facilitator, sugar transporter-like / Sugar (and other) transporter / Sugar transporter, conserved site / Major facilitator superfamily domain / Major facilitator superfamily (MFS) profile. / MFS transporter superfamily
Similarity search - Domain/homology
Solute carrier family 2, facilitated glucose transporter member 9
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.51 Å
AuthorsPan XJ / Shen ZL / Xu L / Huang GXY
Funding support China, 2 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32322039 China
National Natural Science Foundation of China (NSFC)32271252 China
CitationJournal: Nat Commun / Year: 2024
Title: Structural basis for urate recognition and apigenin inhibition of human GLUT9.
Authors: Zilin Shen / Li Xu / Tong Wu / Huan Wang / Qifan Wang / Xiaofei Ge / Fang Kong / Gaoxingyu Huang / Xiaojing Pan /
Abstract: Urate, the physiological form of uric acid and a potent antioxidant in serum, plays a pivotal role in scavenging reactive oxygen species. Yet excessive accumulation of urate, known as hyperuricemia, ...Urate, the physiological form of uric acid and a potent antioxidant in serum, plays a pivotal role in scavenging reactive oxygen species. Yet excessive accumulation of urate, known as hyperuricemia, is the primary risk factor for the development of gout. The high-capacity urate transporter GLUT9 represents a promising target for gout treatment. Here, we present cryo-electron microscopy structures of human GLUT9 in complex with urate or its inhibitor apigenin at overall resolutions of 3.5 Å and 3.3 Å, respectively. In both structures, GLUT9 exhibits an inward open conformation, wherein the substrate binding pocket faces the intracellular side. These structures unveil the molecular basis for GLUT9's substrate preference of urate over glucose, and show that apigenin acts as a competitive inhibitor by occupying the substrate binding site. Our findings provide critical information for the development of specific inhibitors targeting GLUT9 as potential therapeutics for gout and hyperuricemia.
History
DepositionFeb 1, 2024-
Header (metadata) releaseJun 19, 2024-
Map releaseJun 19, 2024-
UpdateJun 19, 2024-
Current statusJun 19, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_38966.png

Downloads & links

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Map

FileDownload / File: emd_38966.map.gz / Format: CCP4 / Size: 27 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryo-EM structure of human urate transporter GLUT9 bound to substrate urate in detergent micelles
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.1 Å/pix.
x 192 pix.
= 210.797 Å		1.1 Å/pix.
x 192 pix.
= 210.797 Å		1.1 Å/pix.
x 192 pix.
= 210.797 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.0979 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.711
Minimum - Maximum-7.1605186 - 13.634634999999999
Average (Standard dev.)0.007353338 (±0.17137711)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions192192192
Spacing192192192
CellA=B=C: 210.79681 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_38966_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_38966_half_map_2.map
Projections & Slices
AxesZYX

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Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : GLUT9 in complex with urate

EntireName: GLUT9 in complex with urate
Components
  • Complex: GLUT9 in complex with urate
    • Protein or peptide: Solute carrier family 2, facilitated glucose transporter member 9
  • Ligand: URIC ACID

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Supramolecule #1: GLUT9 in complex with urate

SupramoleculeName: GLUT9 in complex with urate / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Solute carrier family 2, facilitated glucose transporter member 9

MacromoleculeName: Solute carrier family 2, facilitated glucose transporter member 9
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 63.21509 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MASWSHPQFE KGGGARGGSG GGSWSHPQFE KGFDYKDDDD KGTARKQNRN SKELGLVPLT DDTSHAGPPG PGRALLECDH LRSGVPGGR RRKDWSCSLL VASLAGAFGS SFLYGYNLSV VNAPTPYIKA FYNESWERRH GRPIDPDTLT LLWSVTVSIF A IGGLVGTL ...String:
MASWSHPQFE KGGGARGGSG GGSWSHPQFE KGFDYKDDDD KGTARKQNRN SKELGLVPLT DDTSHAGPPG PGRALLECDH LRSGVPGGR RRKDWSCSLL VASLAGAFGS SFLYGYNLSV VNAPTPYIKA FYNESWERRH GRPIDPDTLT LLWSVTVSIF A IGGLVGTL IVKMIGKVLG RKHTLLANNG FAISAALLMA CSLQAGAFEM LIVGRFIMGI DGGVALSVLP MYLSEISPKE IR GSLGQVT AIFICIGVFT GQLLGLPELL GKESTWPYLF GVIVVPAVVQ LLSLPFLPDS PRYLLLEKHN EARAVKAFQT FLG KADVSQ EVEEVLAESR VQRSIRLVSV LELLRAPYVR WQVVTVIVTM ACYQLCGLNA IWFYTNSIFG KAGIPPAKIP YVTL STGGI ETLAAVFSGL VIEHLGRRPL LIGGFGLMGL FFGTLTITLT LQDHAPWVPY LSIVGILAII ASFCSGPGGI PFILT GEFF QQSQRPAAFI IAGTVNWLSN FAVGLLFPFI QKSLDTYCFL VFATICITGA IYLYFVLPET KNRTYAEISQ AFSKRN KAY PPEEKIDSAV TDGKINGRP

UniProtKB: Solute carrier family 2, facilitated glucose transporter member 9

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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 / 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

Concentration1 mg/mL
BufferpH: 6
VitrificationCryogen name: ETHANE / Chamber humidity: 100 %

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 1.8 µm / Nominal defocus min: 1.5 µm
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average exposure time: 2.56 sec. / Average electron dose: 50.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
Initial angle assignmentType: PROJECTION MATCHING
Final angle assignmentType: PROJECTION MATCHING
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.51 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 810830
FSC plot (resolution estimation)

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