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- EMDB-62696: structure of MCT2-embigin-AR-C155858 complex -

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Basic information

Entry
Database: EMDB / ID: EMD-62696
Titlestructure of MCT2-embigin-AR-C155858 complex
Map data
Sample
  • Complex: MCT2-embigin-AR-C155858
    • Protein or peptide: Embigin
    • Protein or peptide: Monocarboxylate transporter 2
  • Ligand: AR-C155858
Keywordstransporter / monocarboxylate / cancer / drug target / TRANSPORT PROTEIN
Function / homology
Function and homology information


pyruvate secondary active transmembrane transporter activity / lactate transmembrane transport / plasma membrane lactate transport / pyruvate transmembrane transport / lactate transmembrane transporter activity / Proton-coupled monocarboxylate transport / pyruvate transmembrane transporter activity / dendrite self-avoidance / cell-cell adhesion mediator activity / symporter activity ...pyruvate secondary active transmembrane transporter activity / lactate transmembrane transport / plasma membrane lactate transport / pyruvate transmembrane transport / lactate transmembrane transporter activity / Proton-coupled monocarboxylate transport / pyruvate transmembrane transporter activity / dendrite self-avoidance / cell-cell adhesion mediator activity / symporter activity / homophilic cell-cell adhesion / parallel fiber to Purkinje cell synapse / transport across blood-brain barrier / axon guidance / hippocampal mossy fiber to CA3 synapse / postsynaptic density membrane / Schaffer collateral - CA1 synapse / basolateral plasma membrane / axon / synapse / glutamatergic synapse / nucleoplasm / identical protein binding / plasma membrane / cytosol
Similarity search - Function
Monocarboxylate transporter / : / Major facilitator superfamily / Major Facilitator Superfamily / Major facilitator superfamily domain / Major facilitator superfamily (MFS) profile. / Immunoglobulin I-set / Immunoglobulin I-set domain / MFS transporter superfamily / Immunoglobulin subtype ...Monocarboxylate transporter / : / Major facilitator superfamily / Major Facilitator Superfamily / Major facilitator superfamily domain / Major facilitator superfamily (MFS) profile. / Immunoglobulin I-set / Immunoglobulin I-set domain / MFS transporter superfamily / Immunoglobulin subtype / Immunoglobulin / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Immunoglobulin-like fold
Similarity search - Domain/homology
Monocarboxylate transporter 2 / Embigin
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsXu B / Wang Y
Funding support China, 1 items
OrganizationGrant numberCountry
Ministry of Science and Technology (MoST, China) China
CitationJournal: EMBO Rep / Year: 2025
Title: Structure-guided screening identifies Tucatinib as dual inhibitor for MCT1/2.
Authors: Binghong Xu / Xiaoyu Zhou / Yuanyue Shan / Sai Shi / Jiachen Li / Qinqin Liang / Ziyu Wang / Mingfeng Zhang / Yaxin Wang / Duanqing Pei / Sheng Ye /
Abstract: Cell surface glycoproteins Basigin or embigin form heterodimers with monocarboxylate transporters (MCTs), enhancing their membrane trafficking and modulating their transport functions. Cancer cells ...Cell surface glycoproteins Basigin or embigin form heterodimers with monocarboxylate transporters (MCTs), enhancing their membrane trafficking and modulating their transport functions. Cancer cells often reprogram their metabolism and depend on proton-coupled lactate transport mediated by MCTs to sustain their glycolytic state and to maintain intracellular pH. A deeper understanding of MCTs regulation may open avenues for the development of novel inhibitors, potentially applicable in clinical settings. Here, we determine the cryo-EM structures of the human MCT2-embigin complex in both apo and AR-C155858-bound states and observe that embigin engages in extensive interactions with MCT2, facilitating its localization to the plasma membrane and substrate transport. Given the high structural conservation among MCTs, we conduct virtual screening based on MCT1/2 structures and identify Tucatinib as an effective inhibitor of pyruvate transport mediated by both MCT1 and MCT2. We show that Tucatinib potently inhibits the proliferation and migration of cervical tumor cells in vitro and tumor growth in a mouse xenograft model, while exhibiting excellent biological safety. These findings offer molecular insights into the structural and functional mechanism of MCT2 and identify Tucatinib as novel dual inhibitor of both transporters.
History
DepositionDec 12, 2024-
Header (metadata) releaseDec 24, 2025-
Map releaseDec 24, 2025-
UpdateJan 7, 2026-
Current statusJan 7, 2026Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_62696.png

Downloads & links

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Map

FileDownload / File: emd_62696.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.85 Å/pix.
x 320 pix.
= 271.68 Å		0.85 Å/pix.
x 320 pix.
= 271.68 Å		0.85 Å/pix.
x 320 pix.
= 271.68 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.849 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.2
Minimum - Maximum-0.6405008 - 1.6160142
Average (Standard dev.)-0.000021953716 (±0.032268524)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 271.68 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_62696_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_62696_half_map_2.map
Projections & Slices
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Histogram

Histogram (log scale)

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Sample components

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Entire : MCT2-embigin-AR-C155858

EntireName: MCT2-embigin-AR-C155858
Components
  • Complex: MCT2-embigin-AR-C155858
    • Protein or peptide: Embigin
    • Protein or peptide: Monocarboxylate transporter 2
  • Ligand: AR-C155858

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Supramolecule #1: MCT2-embigin-AR-C155858

SupramoleculeName: MCT2-embigin-AR-C155858 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Embigin

MacromoleculeName: Embigin / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 36.921844 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MRALPGLLEA RARTPRLLLL QCLLAAARPS SADGSAPDSP FTSPPLREEI MANNFSLESH NISLTEHSSM PVEKNITLER PSNVNLTCQ FTTSGDLNAV NVTWKKDGEQ LENNYLVSAT GSTLYTQYRF TIINSKQMGS YSCFFREEKE QRGTFNFKVP E LHGKNKPL ...String:
MRALPGLLEA RARTPRLLLL QCLLAAARPS SADGSAPDSP FTSPPLREEI MANNFSLESH NISLTEHSSM PVEKNITLER PSNVNLTCQ FTTSGDLNAV NVTWKKDGEQ LENNYLVSAT GSTLYTQYRF TIINSKQMGS YSCFFREEKE QRGTFNFKVP E LHGKNKPL ISYVGDSTVL TCKCQNCFPL NWTWYSSNGS VKVPVGVQMN KYVINGTYAN ETKLKITQLL EEDGESYWCR AL FQLGESE EHIELVVLSY LVPLKPFLVI VAEVILLVAT ILLCEKYTQK KKKHSDEGKE FEQIEQLKSD DSNGIENNVP RHR KNESLG Q

UniProtKB: Embigin

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Macromolecule #2: Monocarboxylate transporter 2

MacromoleculeName: Monocarboxylate transporter 2 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 52.246957 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MPPMPSAPPV HPPPDGGWGW IVVGAAFISI GFSYAFPKAV TVFFKEIQQI FHTTYSEIAW ISSIMLAVMY AGGPVSSVLV NKYGSRPVV IAGGLLCCLG MVLASFSSSV VQLYLTMGFI TGLGLAFNLQ PALTIIGKYF YRKRPMANGL AMAGSPVFLS S LAPFNQYL ...String:
MPPMPSAPPV HPPPDGGWGW IVVGAAFISI GFSYAFPKAV TVFFKEIQQI FHTTYSEIAW ISSIMLAVMY AGGPVSSVLV NKYGSRPVV IAGGLLCCLG MVLASFSSSV VQLYLTMGFI TGLGLAFNLQ PALTIIGKYF YRKRPMANGL AMAGSPVFLS S LAPFNQYL FNTFGWKGSF LILGSLLLNA CVAGSLMRPL GPNQTTSKSK NKTGKTEDDS SPKKIKTKKS TWEKVNKYLD FS LFKHRGF LIYLSGNVIM FLGFFAPIIF LAPYAKDQGI DEYSAAFLLS VMAFVDMFAR PSVGLIANSK YIRPRIQYFF SFA IMFNGV CHLLCPLAQD YTSLVLYAVF FGLGFGSVSS VLFETLMDLV GAPRFSSAVG LVTIVECGPV LLGPPLAGKL VDLT GEYKY MYMSCGAIVV AASVWLLIGN AINYRLLAKE RKEENARQKT RESEPLSKSK HSEDVNVKVS NAQSVTSERE TNI

UniProtKB: Monocarboxylate transporter 2

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Macromolecule #3: AR-C155858

MacromoleculeName: AR-C155858 / type: ligand / ID: 3 / Number of copies: 1 / Formula: A1EH2
Molecular weightTheoretical: 461.535 Da

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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 TALOS ARCTICA
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.5 µm
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

9l0b

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 700440
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION

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