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- EMDB-30019: Cryo-EM structure of the human MCT1/Basigin-2 complex in the pres... -

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Basic information

Entry
Database: EMDB / ID: EMD-30019
TitleCryo-EM structure of the human MCT1/Basigin-2 complex in the presence of anti-cancer drug candidate AZD3965 in the outward-open conformation.
Map dataCryo-EM structure of human MCT1 in complex with Basigin-2 in the presence of AZD3965
Sample
  • Complex: MCT1/Basigin-2 complex
    • Protein or peptide: Monocarboxylate transporter 1
    • Protein or peptide: Basigin
  • Ligand: 3-methyl-5-[[(4~{R})-4-methyl-4-oxidanyl-1,2-oxazolidin-2-yl]carbonyl]-6-[[5-methyl-3-(trifluoromethyl)-1~{H}-pyrazol-4-yl]methyl]-1-propan-2-yl-thieno[2,3-d]pyrimidine-2,4-dione
KeywordsProton-coupled monocarboxylate transporter / MCT1 / Basigin / anti-cancer / AZD3965 / BAY-8002 / 7ACC2 / single particle cryo-EM / latate transporter / TRANSPORT PROTEIN
Function / homology
Function and homology information


mevalonate transmembrane transporter activity / mevalonate transport / behavioral response to nutrient / monocarboxylic acid transmembrane transporter activity / plasma membrane lactate transport / pyruvate transmembrane transport / 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 / behavioral response to nutrient / monocarboxylic acid transmembrane transporter activity / plasma membrane lactate transport / pyruvate transmembrane transport / 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 / succinate transmembrane transporter activity / pyruvate catabolic process / carboxylic acid transmembrane transport / carboxylic acid transmembrane transporter activity / positive regulation of matrix metallopeptidase secretion / acrosomal membrane / organic cyclic compound binding / response to mercury ion / endothelial tube morphogenesis / neural retina development / photoreceptor cell maintenance / centrosome cycle / Basigin interactions / response to food / Aspirin ADME / odontogenesis of dentin-containing tooth / D-mannose binding / cellular response to organic cyclic compound / decidualization / transport across blood-brain barrier / positive regulation of vascular endothelial growth factor production / photoreceptor outer segment / lateral plasma membrane / Integrin cell surface interactions / response to cAMP / neutrophil chemotaxis / embryo implantation / Degradation of the extracellular matrix / regulation of insulin secretion / photoreceptor inner segment / positive regulation of endothelial cell migration / basal plasma membrane / protein localization to plasma membrane / lipid metabolic process / sarcolemma / response to peptide hormone / positive regulation of interleukin-6 production / melanosome / cell junction / glucose homeostasis / signaling receptor activity / virus receptor activity / 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 / intracellular membrane-bounded organelle / focal adhesion / centrosome / synapse / 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. / MFS transporter superfamily / Immunoglobulin domain / Immunoglobulin subtype 2 / Immunoglobulin C-2 Type ...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: 3.2 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
DepositionFeb 16, 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: 1.14
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 1.14
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6lyy
  • Surface level: 1.14
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-6lyy
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_30019.png

Downloads & links

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Map

FileDownload / File: emd_30019.map.gz / Format: CCP4 / Size: 30.5 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryo-EM structure of human MCT1 in complex with Basigin-2 in the presence of AZD3965
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.09 Å/pix.
x 200 pix.
= 218.2 Å		1.09 Å/pix.
x 200 pix.
= 218.2 Å		1.09 Å/pix.
x 200 pix.
= 218.2 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.091 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 1.14 / Movie #1: 1.14
Minimum - Maximum-3.3565252 - 5.125559
Average (Standard dev.)0.006952484 (±0.12015364)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions200200200
Spacing200200200
CellA=B=C: 218.2 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.0911.0911.091
M x/y/z200200200
origin x/y/z0.0000.0000.000
length x/y/z218.200218.200218.200
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS200200200
D min/max/mean-3.3575.1260.007

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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: 3-methyl-5-[[(4~{R})-4-methyl-4-oxidanyl-1,2-oxazolidin-2-yl]carbonyl]-6-[[5-methyl-3-(trifluoromethyl)-1~{H}-pyrazol-4-yl]methyl]-1-propan-2-yl-thieno[2,3-d]pyrimidine-2,4-dione

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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: Spodoptera frugiperda (fall armyworm)
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: Spodoptera frugiperda (fall armyworm)
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: 3-methyl-5-[[(4~{R})-4-methyl-4-oxidanyl-1,2-oxazolidin-2-yl]carb...

MacromoleculeName: 3-methyl-5-[[(4~{R})-4-methyl-4-oxidanyl-1,2-oxazolidin-2-yl]carbonyl]-6-[[5-methyl-3-(trifluoromethyl)-1~{H}-pyrazol-4-yl]methyl]-1-propan-2-yl-thieno[2,3-d]pyrimidine-2,4-dione
type: ligand / ID: 3 / Number of copies: 1 / Formula: EY0
Molecular weightTheoretical: 515.506 Da
Chemical component information

ChemComp-EY0:
3-methyl-5-[[(4~{R})-4-methyl-4-oxidanyl-1,2-oxazolidin-2-yl]carbonyl]-6-[[5-methyl-3-(trifluoromethyl)-1~{H}-pyrazol-4-yl]methyl]-1-propan-2-yl-thieno[2,3-d]pyrimidine-2,4-dione

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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
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 37.6 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 0.01 mm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 2.12) / Number images used: 1326285
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 3.07)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 2.12)

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