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- PDB-8y65: Cryo-EM structure of human urate transporter GLUT9 bound to subst... -

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Basic information

Entry
Database: PDB / ID: 8y65
TitleCryo-EM structure of human urate transporter GLUT9 bound to substrate urate
ComponentsSolute carrier family 2, facilitated glucose transporter member 9
KeywordsTRANSPORT PROTEIN / GLUT9 / Urate
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
URIC ACID / Solute carrier family 2, facilitated glucose transporter member 9
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.51 Å
AuthorsPan, X.J. / Shen, Z.L. / Xu, L. / Huang, G.X.Y.
Funding support China, 2items
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, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jun 19, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Solute carrier family 2, facilitated glucose transporter member 9
hetero molecules


Theoretical massNumber of molelcules
Total (without water)63,3832
Polymers63,2151
Non-polymers1681
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein Solute carrier family 2, facilitated glucose transporter member 9 / Glucose transporter type 9 / GLUT-9 / Urate transporter


Mass: 63215.090 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SLC2A9, GLUT9 / Production host: Homo sapiens (human) / References: UniProt: Q9NRM0
#2: Chemical ChemComp-URC / URIC ACID / 7,9-DIHYDRO-1H-PURINE-2,6,8(3H)-TRIONE


Mass: 168.110 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C5H4N4O3 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: GLUT9 in complex with urate / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 6
SpecimenConc.: 1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE / Humidity: 100 %

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1800 nm / Nominal defocus min: 1500 nm
Image recordingAverage exposure time: 2.56 sec. / Electron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.19.2_4158: / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.51 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 810830 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0023655
ELECTRON MICROSCOPYf_angle_d0.5754989
ELECTRON MICROSCOPYf_dihedral_angle_d3.938498
ELECTRON MICROSCOPYf_chiral_restr0.04592
ELECTRON MICROSCOPYf_plane_restr0.005618

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