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- EMDB-30391: Cryo-EM structure of the human MCT1/Basigin-2 complex in the pres... -

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Basic information

Entry
Database: EMDB / ID: EMD-30391
TitleCryo-EM structure of the human MCT1/Basigin-2 complex in the presence of anti-cancer drug candidate BAY-8002 in the outward-open conformation.
Map dataCryo-EM structure of human MCT1/Basigin-2 complex in the presence of inhibitor BAY-8002 in an outward-open state.
Sample
  • Complex: MCT1/Basigin-2 complex
    • Protein or peptide: Monocarboxylate transporter 1
    • Protein or peptide: Basigin
  • Ligand: 2-[[2-chloranyl-5-(phenylsulfonyl)phenyl]carbonylamino]benzoic acid
KeywordsProton-coupled monocarboxylate transporter / MCT1 / Basigin / anti-cancer drug candidate / AZD3965 / BAY-8002 / 7ACC2 / single particle cryo-EM / latate transporter / TRANSPORT PROTEIN
Function / homology
Function and homology information


mevalonate transmembrane transporter activity / mevalonate transport / plasma membrane lactate transport / behavioral response to nutrient / pyruvate transmembrane transport / monocarboxylic acid transmembrane transporter activity / lactate transmembrane transporter activity / monocarboxylic acid transport / lactate:proton symporter activity / Defective SLC16A1 causes symptomatic deficiency in lactate transport (SDLT) ...mevalonate transmembrane transporter activity / mevalonate transport / plasma membrane lactate transport / behavioral response to nutrient / pyruvate transmembrane transport / monocarboxylic acid transmembrane transporter activity / lactate transmembrane transporter activity / monocarboxylic acid transport / lactate:proton symporter activity / Defective SLC16A1 causes symptomatic deficiency in lactate transport (SDLT) / succinate transmembrane transport / Proton-coupled monocarboxylate transport / pyruvate catabolic process / succinate transmembrane transporter activity / positive regulation of matrix metallopeptidase secretion / acrosomal membrane / carboxylic acid transmembrane transport / carboxylic acid transmembrane transporter activity / response to mercury ion / organic cyclic compound binding / neural retina development / endothelial tube morphogenesis / Pyruvate metabolism / photoreceptor cell maintenance / centrosome cycle / Basigin interactions / response to food / Aspirin ADME / odontogenesis of dentin-containing tooth / mannose binding / regulation of insulin secretion / transport across blood-brain barrier / decidualization / cellular response to organic cyclic compound / photoreceptor outer segment / positive regulation of vascular endothelial growth factor production / lateral plasma membrane / Integrin cell surface interactions / embryo implantation / response to cAMP / photoreceptor inner segment / Degradation of the extracellular matrix / basal plasma membrane / neutrophil chemotaxis / positive regulation of endothelial cell migration / protein localization to plasma membrane / sarcolemma / lipid metabolic process / response to peptide hormone / positive regulation of interleukin-6 production / melanosome / glucose homeostasis / virus receptor activity / signaling receptor activity / cell junction / basolateral plasma membrane / angiogenesis / positive regulation of viral entry into host cell / cell surface receptor signaling pathway / endosome / cadherin binding / apical plasma membrane / Golgi membrane / focal adhesion / intracellular membrane-bounded organelle / centrosome / synapse / endoplasmic reticulum membrane / mitochondrion / extracellular exosome / membrane / identical protein binding / plasma membrane
Similarity search - Function
Monocarboxylate transporter / Major facilitator superfamily / Major Facilitator Superfamily / Major facilitator superfamily domain / Major facilitator superfamily (MFS) profile. / MFS transporter superfamily / Immunoglobulin domain / Immunoglobulin subtype 2 / Immunoglobulin C-2 Type / Immunoglobulin subtype ...Monocarboxylate transporter / Major facilitator superfamily / Major Facilitator Superfamily / Major facilitator superfamily domain / Major facilitator superfamily (MFS) profile. / MFS transporter superfamily / Immunoglobulin domain / 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
Basigin / Monocarboxylate transporter 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.0 Å
AuthorsWang N / Jiang X
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, 2020-
Header (metadata) releaseDec 23, 2020-
Map releaseDec 23, 2020-
UpdateMar 27, 2024-
Current statusMar 27, 2024Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.778
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 0.778
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7ckr
  • Surface level: 0.778
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_30391.png

Downloads & links

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Map

FileDownload / File: emd_30391.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryo-EM structure of human MCT1/Basigin-2 complex in the presence of inhibitor BAY-8002 in an outward-open state.
Voxel sizeX=Y=Z: 0.8433 Å
Density
Contour LevelBy AUTHOR: 0.778 / Movie #1: 0.778
Minimum - Maximum-2.7463152 - 4.049468
Average (Standard dev.)0.003741044 (±0.06992313)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 215.8848 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.843300781250.843300781250.84330078125
M x/y/z256256256
origin x/y/z0.0000.0000.000
length x/y/z215.885215.885215.885
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS256256256
D min/max/mean-2.7464.0490.004

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Supplemental data

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Sample components

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Entire : MCT1/Basigin-2 complex

EntireName: MCT1/Basigin-2 complex
Components
  • Complex: MCT1/Basigin-2 complex
    • Protein or peptide: Monocarboxylate transporter 1
    • Protein or peptide: Basigin
  • Ligand: 2-[[2-chloranyl-5-(phenylsulfonyl)phenyl]carbonylamino]benzoic acid

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Supramolecule #1: MCT1/Basigin-2 complex

SupramoleculeName: MCT1/Basigin-2 complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Monocarboxylate transporter 1

MacromoleculeName: Monocarboxylate transporter 1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 53.992852 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MPPAVGGPVG YTPPDGGWGW AVVIGAFISI GFSYAFPKSI TVFFKEIEGI FHATTSEVSW ISSIMLAVMY GGGPISSILV NKYGSRIVM IVGGCLSGCG LIAASFCNTV QQLYVCIGVI GGLGLAFNLN PALTMIGKYF YKRRPLANGL AMAGSPVFLC T LAPLNQVF ...String:
MPPAVGGPVG YTPPDGGWGW AVVIGAFISI GFSYAFPKSI TVFFKEIEGI FHATTSEVSW ISSIMLAVMY GGGPISSILV NKYGSRIVM IVGGCLSGCG LIAASFCNTV QQLYVCIGVI GGLGLAFNLN PALTMIGKYF YKRRPLANGL AMAGSPVFLC T LAPLNQVF FGIFGWRGSF LILGGLLLNC CVAGALMRPI GPKPTKAGKD KSKASLEKAG KSGVKKDLHD ANTDLIGRHP KQ EKRSVFQ TINQFLDLTL FTHRGFLLYL SGNVIMFFGL FAPLVFLSSY GKSQHYSSEK SAFLLSILAF VDMVARPSMG LVA NTKPIR PRIQYFFAAS VVANGVCHML APLSTTYVGF CVYAGFFGFA FGWLSSVLFE TLMDLVGPQR FSSAVGLVTI VECC PVLLG PPLLGRLNDM YGDYKYTYWA CGVVLIISGI YLFIGMGINY RLLAKEQKAN EQKKESKEEE TSIDVAGKPN EVTKA AESP DQKDTDGGPK EEESPV

UniProtKB: Monocarboxylate transporter 1

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Macromolecule #2: Basigin

MacromoleculeName: Basigin / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 29.254938 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MAAALFVLLG FALLGTHGAS GAAGTVFTTV EDLGSKILLT CSLNDSATEV TGHRWLKGGV VLKEDALPGQ KTEFKVDSDD QWGEYSCVF LPEPMGTANI QLHGPPRVKA VKSSEHINEG ETAMLVCKSE SVPPVTDWAW YKITDSEDKA LMNGSESRFF V SSSQGRSE ...String:
MAAALFVLLG FALLGTHGAS GAAGTVFTTV EDLGSKILLT CSLNDSATEV TGHRWLKGGV VLKEDALPGQ KTEFKVDSDD QWGEYSCVF LPEPMGTANI QLHGPPRVKA VKSSEHINEG ETAMLVCKSE SVPPVTDWAW YKITDSEDKA LMNGSESRFF V SSSQGRSE LHIENLNMEA DPGQYRCNGT SSKGSDQAII TLRVRSHLAA LWPFLGIVAE VLVLVTIIFI YEKRRKPEDV LD DDDAGSA PLKSSGQHQN DKGKNVRQRN SS

UniProtKB: Basigin

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Macromolecule #3: 2-[[2-chloranyl-5-(phenylsulfonyl)phenyl]carbonylamino]benzoic acid

MacromoleculeName: 2-[[2-chloranyl-5-(phenylsulfonyl)phenyl]carbonylamino]benzoic acid
type: ligand / ID: 3 / Number of copies: 1 / Formula: G5O
Molecular weightTheoretical: 415.847 Da
Chemical component information

ChemComp-G5O:
2-[[2-chloranyl-5-(phenylsulfonyl)phenyl]carbonylamino]benzoic acid

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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

Concentration5 mg/mL
BufferpH: 8
Details: 25 mM Tris pH 8.0, 150 mM NaCl, and 0.02% (w/v) GDN
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm
Specialist opticsEnergy filter - Name: GIF Quantum LS / Energy filter - Slit width: 30 eV
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Number real images: 10549 / Average electron dose: 37.6 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 2.14)
Final 3D classificationNumber classes: 3 / Software - Name: cryoSPARC (ver. 2.14)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 2.14)
Final reconstructionNumber classes used: 1 / Applied symmetry - Point group: C1 (asymmetric) / Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 2.14) / Number images used: 494077

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: RIGID BODY FIT / Overall B value: 110 / Target criteria: correlation coefficient
Output model

PDB-7ckr:
Cryo-EM structure of the human MCT1/Basigin-2 complex in the presence of anti-cancer drug candidate BAY-8002 in the outward-open conformation.

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