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- PDB-8y66: Cryo-EM structure of human urate transporter GLUT9 bound to inhib... -

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Entry
Database: PDB / ID: 8y66
TitleCryo-EM structure of human urate transporter GLUT9 bound to inhibitor apigenin
ComponentsSolute carrier family 2, facilitated glucose transporter member 9
KeywordsTRANSPORT PROTEIN / GLUT9 / inhibitor / apigenin
Function / homology
Function and homology information


Defective SLC2A9 causes hypouricemia renal 2 (RHUC2) / fructose transmembrane transporter activity / fructose transmembrane transport / dehydroascorbic acid transport / hexose transmembrane transport / carbohydrate:proton symporter activity / Cellular hexose transport / D-glucose transmembrane transporter activity / D-glucose transmembrane transport / urate transport ...Defective SLC2A9 causes hypouricemia renal 2 (RHUC2) / fructose transmembrane transporter activity / fructose transmembrane transport / dehydroascorbic acid transport / hexose transmembrane transport / carbohydrate:proton symporter activity / Cellular hexose transport / D-glucose transmembrane transporter activity / D-glucose transmembrane transport / urate transport / urate metabolic process / urate transmembrane transporter activity / D-glucose import / 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. / Sugar transporter, conserved site / Major facilitator, sugar transporter-like / Sugar (and other) transporter / Major facilitator superfamily domain / Major facilitator superfamily (MFS) profile. / MFS transporter superfamily
Similarity search - Domain/homology
Chem-AGI / Solute carrier family 2, facilitated glucose transporter member 9
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.28 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)63,4852
Polymers63,2151
Non-polymers2701
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-AGI / 5,7-dihydroxy-2-(4-hydroxyphenyl)-4H-chromen-4-one / Apigenin


Mass: 270.237 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H10O5 / 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 inhibitor apigenin / 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: 3.28 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 296259 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0033697
ELECTRON MICROSCOPYf_angle_d0.6325038
ELECTRON MICROSCOPYf_dihedral_angle_d5.043505
ELECTRON MICROSCOPYf_chiral_restr0.044592
ELECTRON MICROSCOPYf_plane_restr0.005623

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