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- PDB-7cko: Cryo-EM structure of the human MCT1/Basigin-2 complex in the pres... -

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Basic information

Entry
Database: PDB / ID: 7cko
TitleCryo-EM structure of the human MCT1/Basigin-2 complex in the presence of anti-cancer drug candidate 7ACC2 in the inward-open conformation
Components
  • Basigin
  • Monocarboxylate transporter 1
KeywordsTRANSPORT PROTEIN / Proton-coupled monocarboxylate transporter / MCT1 / Basigin / AZD3965 / single particle cryo-EM / latate transporter
Function / homology
Function and homology information


mevalonate transmembrane transporter activity / mevalonate transport / behavioral response to nutrient / plasma membrane lactate transport / pyruvate transmembrane transport / lactate transmembrane transporter activity / lactate:proton symporter activity / Defective SLC16A1 causes symptomatic deficiency in lactate transport (SDLT) / Proton-coupled monocarboxylate transport / succinate transmembrane transport ...mevalonate transmembrane transporter activity / mevalonate transport / behavioral response to nutrient / plasma membrane lactate transport / pyruvate transmembrane transport / lactate transmembrane transporter activity / lactate:proton symporter activity / Defective SLC16A1 causes symptomatic deficiency in lactate transport (SDLT) / Proton-coupled monocarboxylate transport / succinate transmembrane transport / monocarboxylic acid transmembrane transporter activity / monocarboxylic acid transport / positive regulation of matrix metallopeptidase secretion / succinate transmembrane transporter activity / carboxylic acid transmembrane transport / carboxylic acid transmembrane transporter activity / dendrite self-avoidance / acrosomal membrane / cell-cell adhesion mediator activity / pyruvate catabolic process / endothelial tube morphogenesis / response to mercury ion / neural retina development / photoreceptor cell maintenance / centrosome cycle / Basigin interactions / response to food / Aspirin ADME / D-mannose binding / homophilic cell-cell adhesion / odontogenesis of dentin-containing tooth / decidualization / positive regulation of vascular endothelial growth factor production / lateral plasma membrane / response to cAMP / photoreceptor outer segment / Integrin cell surface interactions / transport across blood-brain barrier / Degradation of the extracellular matrix / neutrophil chemotaxis / photoreceptor inner segment / embryo implantation / positive regulation of endothelial cell migration / regulation of insulin secretion / axon guidance / basal plasma membrane / protein localization to plasma membrane / response to peptide hormone / sarcolemma / positive regulation of interleukin-6 production / lipid metabolic process / cell junction / melanosome / glucose homeostasis / signaling receptor activity / virus receptor activity / angiogenesis / basolateral plasma membrane / positive regulation of viral entry into host cell / cell surface receptor signaling pathway / endosome / apical plasma membrane / cadherin binding / Golgi membrane / axon / focal adhesion / intracellular membrane-bounded organelle / synapse / centrosome / endoplasmic reticulum membrane / mitochondrion / extracellular exosome / identical protein binding / membrane / plasma membrane
Similarity search - Function
Monocarboxylate transporter / : / Major facilitator superfamily / Major Facilitator Superfamily / Major facilitator superfamily domain / Major facilitator superfamily (MFS) profile. / Immunoglobulin domain / MFS transporter superfamily / Immunoglobulin subtype 2 / Immunoglobulin C-2 Type ...Monocarboxylate transporter / : / Major facilitator superfamily / Major Facilitator Superfamily / Major facilitator superfamily domain / Major facilitator superfamily (MFS) profile. / Immunoglobulin domain / MFS transporter superfamily / Immunoglobulin subtype 2 / Immunoglobulin C-2 Type / Immunoglobulin subtype / Immunoglobulin / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Immunoglobulin-like fold
Similarity search - Domain/homology
Chem-G5L / Basigin / Monocarboxylate transporter 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.95 Å
AuthorsWang, N. / Jiang, X. / Zhang, S. / Zhu, A. / Yuan, Y. / Lei, J. / Yan, C.
CitationJournal: Cell / Year: 2021
Title: Structural basis of human monocarboxylate transporter 1 inhibition by anti-cancer drug candidates.
Authors: Nan Wang / Xin Jiang / Shuo Zhang / Angqi Zhu / Yafei Yuan / Hanwen Xu / Jianlin Lei / Chuangye Yan /
Abstract: Proton-coupled monocarboxylate transporters MCT1-4 catalyze the transmembrane movement of metabolically essential monocarboxylates and have been targeted for cancer treatment because of their ...Proton-coupled monocarboxylate transporters MCT1-4 catalyze the transmembrane movement of metabolically essential monocarboxylates and have been targeted for cancer treatment because of their enhanced expression in various tumors. Here, we report five cryo-EM structures, at resolutions of 3.0-3.3 Å, of human MCT1 bound to lactate or inhibitors in the presence of Basigin-2, a single transmembrane segment (TM)-containing chaperon. MCT1 exhibits similar outward-open conformations when complexed with lactate or the inhibitors BAY-8002 and AZD3965. In the presence of the inhibitor 7ACC2 or with the neutralization of the proton-coupling residue Asp309 by Asn, similar inward-open structures were captured. Complemented by structural-guided biochemical analyses, our studies reveal the substrate binding and transport mechanism of MCTs, elucidate the mode of action of three anti-cancer drug candidates, and identify the determinants for subtype-specific sensitivities to AZD3965 by MCT1 and MCT4. These findings lay out an important framework for structure-guided drug discovery targeting MCTs.
History
DepositionJul 18, 2020Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Dec 23, 2020Provider: repository / Type: Initial release
Revision 1.1Jan 6, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.journal_id_CSD ..._citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Feb 10, 2021Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.year
Revision 1.3Mar 27, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

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Assembly

Deposited unit
A: Monocarboxylate transporter 1
B: Basigin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)83,5573
Polymers83,2482
Non-polymers3091
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area1320 Å2
ΔGint-13 kcal/mol
Surface area28340 Å2

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Components

#1: Protein Monocarboxylate transporter 1 / MCT 1 / Solute carrier family 16 member 1


Mass: 53992.852 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SLC16A1, MCT1 / Production host: Homo sapiens (human) / References: UniProt: P53985
#2: Protein Basigin / 5F7 / Collagenase stimulatory factor / Extracellular matrix metalloproteinase inducer / EMMPRIN / ...5F7 / Collagenase stimulatory factor / Extracellular matrix metalloproteinase inducer / EMMPRIN / Leukocyte activation antigen M6 / OK blood group antigen / Tumor cell-derived collagenase stimulatory factor / TCSF


Mass: 29254.938 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BSG, UNQ6505/PRO21383 / Production host: Homo sapiens (human) / References: UniProt: P35613
#3: Chemical ChemComp-G5L / 7-[methyl-(phenylmethyl)amino]-2-oxidanylidene-chromene-3-carboxylic acid


Mass: 309.316 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H15NO4 / 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: MCT1/Basigin-2 complex / Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 8
Details: 25 mM Tris pH 8.0, 150 mM NaCl, and 0.02% (w/v) GDN
SpecimenConc.: 5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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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 / Cs: 2.7 mm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 37.6 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)
EM imaging opticsEnergyfilter name: GIF Quantum LS / Energyfilter slit width: 30 eV

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Processing

SoftwareName: PHENIX / Version: dev_3707: / Classification: refinement
EM software
IDNameVersionCategory
4GctfCTF correction
9PHENIXmodel refinement
10RELION3.07initial Euler assignment
11cryoSPARC2.12final Euler assignment
12cryoSPARC2.12classification
13cryoSPARC2.143D reconstruction
CTF correctionType: NONE
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 2.95 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 533887 / Symmetry type: POINT
RefinementHighest resolution: 2.95 Å
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0093227
ELECTRON MICROSCOPYf_angle_d0.8594383
ELECTRON MICROSCOPYf_dihedral_angle_d13.79441
ELECTRON MICROSCOPYf_chiral_restr0.124494
ELECTRON MICROSCOPYf_plane_restr0.006537

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