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- PDB-9l0c: structure of MCT2-embigin-AR-C155858 complex -

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Basic information

Entry
Database: PDB / ID: 9l0c
Titlestructure of MCT2-embigin-AR-C155858 complex
Components
  • Embigin
  • Monocarboxylate transporter 2
KeywordsTRANSPORT PROTEIN / transporter / monocarboxylate / cancer / drug target
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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsXu, B. / Wang, Y.
Funding support China, 1items
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, 2024Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Dec 24, 2025Provider: repository / Type: Initial release
Revision 1.0Dec 24, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: Embigin
A: Monocarboxylate transporter 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)89,6303
Polymers89,1692
Non-polymers4621
Water00
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

#1: Protein Embigin


Mass: 36921.844 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EMB / Production host: Homo sapiens (human) / References: UniProt: Q6PCB8
#2: Protein Monocarboxylate transporter 2 / MCT 2 / Solute carrier family 16 member 7


Mass: 52246.957 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SLC16A7, MCT2 / Production host: Homo sapiens (human) / References: UniProt: O60669
#3: Chemical ChemComp-A1EH2 / AR-C155858


Mass: 461.535 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H27N5O5S
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: MCT2-embigin-AR-C155858 / Type: COMPLEX / Entity ID: #1-#2 / Source: MULTIPLE SOURCES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company
MicroscopyModel: FEI TALOS ARCTICA
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 1500 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.20.1_4487 / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 700440 / Symmetry type: POINT
RefinementHighest resolution: 3.2 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)

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