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- PDB-9r1f: Cryo-EM structure of human MATE1 in complex with metformin -

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Basic information

Entry
Database: PDB / ID: 9r1f
TitleCryo-EM structure of human MATE1 in complex with metformin
Components
  • Heavy chain of Fab
  • Light chain of Fab
  • Multidrug and toxin extrusion protein 1
KeywordsTRANSPORT PROTEIN / SLC47A1 / ligand / Fab / multidrug transporter
Function / homology
Function and homology information


L-arginine import across plasma membrane / polyspecific organic cation:proton antiporter activity / L-alpha-amino acid transmembrane transport / putrescine transmembrane transporter activity / L-arginine transmembrane transporter activity / organic cation transport / : / : / putrescine transport / thiamine transmembrane transporter activity ...L-arginine import across plasma membrane / polyspecific organic cation:proton antiporter activity / L-alpha-amino acid transmembrane transport / putrescine transmembrane transporter activity / L-arginine transmembrane transporter activity / organic cation transport / : / : / putrescine transport / thiamine transmembrane transporter activity / L-amino acid transmembrane transporter activity / amino acid import across plasma membrane / xenobiotic transmembrane transport / xenobiotic detoxification by transmembrane export across the plasma membrane / antiporter activity / xenobiotic transport / transmembrane transporter activity / xenobiotic transmembrane transporter activity / transmembrane transport / basolateral plasma membrane / apical plasma membrane / membrane / plasma membrane
Similarity search - Function
Multidrug and toxic compound extrusion family, eukaryotic / Multi antimicrobial extrusion protein / MatE
Similarity search - Domain/homology
CHOLESTEROL / Metformin / Multidrug and toxin extrusion protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.31 Å
AuthorsRomane, K. / Peteani, G. / Mukherjee, S. / Kowal, J. / Rossi, L. / Hou, J. / Kossiakoff, A. / Lemmin, T. / Locher, K.P.
Funding support Switzerland, 2items
OrganizationGrant numberCountry
Swiss National Science Foundation51NF40-185544 Switzerland
Swiss National Science Foundation214834 Switzerland
CitationJournal: Nat Commun / Year: 2025
Title: Structural basis of drug recognition by human MATE1 transporter.
Authors: Ksenija Romane / Giulia Peteani / Somnath Mukherjee / Julia Kowal / Lorenzo Rossi / Jingkai Hou / Anthony A Kossiakoff / Thomas Lemmin / Kaspar P Locher /
Abstract: Human MATE1 (multidrug and toxin extrusion protein 1) is highly expressed in the kidney and liver, where it mediates the final step in the excretion of a broad range of cationic drugs, including the ...Human MATE1 (multidrug and toxin extrusion protein 1) is highly expressed in the kidney and liver, where it mediates the final step in the excretion of a broad range of cationic drugs, including the antidiabetic drug metformin, into the urine and bile. This transport process is essential for drug clearance and also affects therapeutic efficacy. To understand the molecular basis of drug recognition by hMATE1, we determined cryo-electron microscopy structures of the transporter in complex with the substrates 1-methyl-4-phenylpyridinium (MPP) and metformin and with the inhibitor cimetidine. The structures reveal a shared binding site located in a negatively charged pocket in the C-lobe of the protein. We functionally validated key interactions using radioactivity-based cellular uptake assays using hMATE1 mutants. Molecular dynamics simulations provide insights into the different binding modes and dynamic behaviour of the ligands within the pocket. Collectively, these findings define the structural basis of hMATE1 substrate specificity and shed light on its role in drug transport and drug-drug interactions.
History
DepositionApr 26, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 5, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Multidrug and toxin extrusion protein 1
H: Heavy chain of Fab
L: Light chain of Fab
hetero molecules


Theoretical massNumber of molelcules
Total (without water)111,4219
Polymers109,3583
Non-polymers2,0626
Water70339
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Multidrug and toxin extrusion protein 1 / MATE-1 / hMATE-1 / Solute carrier family 47 member 1


Mass: 61967.766 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SLC47A1, MATE1 / Production host: Homo sapiens (human) / References: UniProt: Q96FL8

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Antibody , 2 types, 2 molecules HL

#2: Antibody Heavy chain of Fab


Mass: 24249.971 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others) / Production host: Escherichia coli (E. coli)
#3: Antibody Light chain of Fab


Mass: 23140.717 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others) / Production host: Escherichia coli (E. coli)

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Non-polymers , 3 types, 45 molecules

#4: Chemical
ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 5 / Source method: isolated from a natural source / Formula: C27H46O
#5: Chemical ChemComp-MF8 / Metformin / N,N-Dimethylimidodicarbonimidic diamide


Mass: 129.164 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: C4H11N5 / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 39 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationY

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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: Human multidrug and toxin extrusion protein (MATE1) in complex with Fab and metformin
Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT
Molecular weightValue: 0.112 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE-PROPANE / Humidity: 100 %

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2400 nm / Nominal defocus min: 600 nm
Specimen holderCryogen: NITROGEN
Image recordingElectron dose: 51 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Num. of grids imaged: 2 / Num. of real images: 26431

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Processing

EM software
IDNameVersionCategory
7Cootmodel fitting
13PHENIX1.21_5207model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.31 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 431222 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 67.13 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00227339
ELECTRON MICROSCOPYf_angle_d0.468310024
ELECTRON MICROSCOPYf_chiral_restr0.03781194
ELECTRON MICROSCOPYf_plane_restr0.00341207
ELECTRON MICROSCOPYf_dihedral_angle_d10.65452818

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