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- EMDB-11666: Nanodisc reconstituted, drug-free human ABCB1 in complex with MRK... -

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Basic information

Entry
Database: EMDB / ID: EMD-11666
TitleNanodisc reconstituted, drug-free human ABCB1 in complex with MRK16 Fab
Map datadrug-free human ABCB1-MRK16-Fab
Sample
  • Complex: Nanodisc reconstituted, drug-free human ABCB1 in complex with MRK16 Fab
    • Complex: Multidrug resistance protein 1
      • Protein or peptide: Multidrug resistance protein 1
    • Complex: MRK16 Fab-fragment light and heavy chain
      • Protein or peptide: MRK16 Fab-fragment light chain
      • Protein or peptide: MRK16 Fab-fragment heavy chain
  • Ligand: CHOLESTEROL
KeywordsP-glycoprotein / MDR1 / nanodisc / TRANSPORT PROTEIN
Function / homology
Function and homology information


carboxylic acid transmembrane transport / carboxylic acid transmembrane transporter activity / hormone transport / cellular response to nonylphenol / cellular response to borneol / response to codeine / response to cyclosporin A / cellular response to mycotoxin / daunorubicin transport / positive regulation of response to drug ...carboxylic acid transmembrane transport / carboxylic acid transmembrane transporter activity / hormone transport / cellular response to nonylphenol / cellular response to borneol / response to codeine / response to cyclosporin A / cellular response to mycotoxin / daunorubicin transport / positive regulation of response to drug / terpenoid transport / ceramide floppase activity / negative regulation of sensory perception of pain / positive regulation of establishment of Sertoli cell barrier / regulation of intestinal absorption / cellular response to external biotic stimulus / response to quercetin / response to antineoplastic agent / ceramide translocation / floppase activity / Abacavir transmembrane transport / establishment of blood-retinal barrier / phosphatidylethanolamine flippase activity / protein localization to bicellular tight junction / phosphatidylcholine floppase activity / external side of apical plasma membrane / Atorvastatin ADME / xenobiotic transport across blood-brain barrier / response to thyroxine / establishment of blood-brain barrier / transepithelial transport / xenobiotic detoxification by transmembrane export across the plasma membrane / export across plasma membrane / P-type phospholipid transporter / cellular response to L-glutamate / response to vitamin A / ABC-type xenobiotic transporter / response to vitamin D / response to glycoside / response to alcohol / response to glucagon / intestinal absorption / ABC-type xenobiotic transporter activity / Prednisone ADME / cellular response to antibiotic / phospholipid translocation / cellular hyperosmotic salinity response / maintenance of blood-brain barrier / cellular response to alkaloid / efflux transmembrane transporter activity / transmembrane transporter activity / xenobiotic transmembrane transporter activity / ATPase-coupled transmembrane transporter activity / cellular response to dexamethasone stimulus / response to cadmium ion / transport across blood-brain barrier / lactation / xenobiotic metabolic process / regulation of chloride transport / response to progesterone / placenta development / stem cell proliferation / cellular response to estradiol stimulus / brush border membrane / female pregnancy / circadian rhythm / ABC-family proteins mediated transport / transmembrane transport / G2/M transition of mitotic cell cycle / cellular response to tumor necrosis factor / cellular response to lipopolysaccharide / response to hypoxia / apical plasma membrane / response to xenobiotic stimulus / ubiquitin protein ligase binding / cell surface / ATP hydrolysis activity / extracellular exosome / ATP binding / membrane / plasma membrane / cytoplasm
Similarity search - Function
Type 1 protein exporter / ABC transporter transmembrane region / ABC transporter type 1, transmembrane domain / ABC transporter integral membrane type-1 fused domain profile. / ABC transporter type 1, transmembrane domain superfamily / ABC transporter-like, conserved site / ABC transporters family signature. / ABC transporter / ABC transporter-like, ATP-binding domain / ATP-binding cassette, ABC transporter-type domain profile. ...Type 1 protein exporter / ABC transporter transmembrane region / ABC transporter type 1, transmembrane domain / ABC transporter integral membrane type-1 fused domain profile. / ABC transporter type 1, transmembrane domain superfamily / ABC transporter-like, conserved site / ABC transporters family signature. / ABC transporter / ABC transporter-like, ATP-binding domain / ATP-binding cassette, ABC transporter-type domain profile. / ATPases associated with a variety of cellular activities / AAA+ ATPase domain / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
ATP-dependent translocase ABCB1
Similarity search - Component
Biological speciesHomo sapiens (human) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.9 Å
AuthorsNosol K / Locher KP
Funding support Switzerland, 1 items
OrganizationGrant numberCountry
Swiss National Science Foundation310030_189111 Switzerland
CitationJournal: Proc Natl Acad Sci U S A / Year: 2020
Title: Cryo-EM structures reveal distinct mechanisms of inhibition of the human multidrug transporter ABCB1.
Authors: Kamil Nosol / Ksenija Romane / Rossitza N Irobalieva / Amer Alam / Julia Kowal / Naoya Fujita / Kaspar P Locher /
Abstract: ABCB1 detoxifies cells by exporting diverse xenobiotic compounds, thereby limiting drug disposition and contributing to multidrug resistance in cancer cells. Multiple small-molecule inhibitors and ...ABCB1 detoxifies cells by exporting diverse xenobiotic compounds, thereby limiting drug disposition and contributing to multidrug resistance in cancer cells. Multiple small-molecule inhibitors and inhibitory antibodies have been developed for therapeutic applications, but the structural basis of their activity is insufficiently understood. We determined cryo-EM structures of nanodisc-reconstituted, human ABCB1 in complex with the Fab fragment of the inhibitory, monoclonal antibody MRK16 and bound to a substrate (the antitumor drug vincristine) or to the potent inhibitors elacridar, tariquidar, or zosuquidar. We found that inhibitors bound in pairs, with one molecule lodged in the central drug-binding pocket and a second extending into a phenylalanine-rich cavity that we termed the "access tunnel." This finding explains how inhibitors can act as substrates at low concentration, but interfere with the early steps of the peristaltic extrusion mechanism at higher concentration. Our structural data will also help the development of more potent and selective ABCB1 inhibitors.
History
DepositionAug 25, 2020-
Header (metadata) releaseOct 14, 2020-
Map releaseOct 14, 2020-
UpdateJul 2, 2025-
Current statusJul 2, 2025Processing site: PDBe / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.014
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by cylindrical radius
  • Surface level: 0.014
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7a65
  • Surface level: 0.014
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_11666.png

Downloads & links

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Map

FileDownload / File: emd_11666.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationdrug-free human ABCB1-MRK16-Fab
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.84 Å/pix.
x 384 pix.
= 322.56 Å		0.84 Å/pix.
x 384 pix.
= 322.56 Å		0.84 Å/pix.
x 384 pix.
= 322.56 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.84 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.015 / Movie #1: 0.014
Minimum - Maximum-0.039262496 - 0.07111042
Average (Standard dev.)0.00000029720186 (±0.0017598394)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 322.56 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.840.840.84
M x/y/z384384384
origin x/y/z0.0000.0000.000
length x/y/z322.560322.560322.560
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ161186271
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS384384384
D min/max/mean-0.0390.0710.000

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Supplemental data

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Sample components

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Entire : Nanodisc reconstituted, drug-free human ABCB1 in complex with MRK...

EntireName: Nanodisc reconstituted, drug-free human ABCB1 in complex with MRK16 Fab
Components
  • Complex: Nanodisc reconstituted, drug-free human ABCB1 in complex with MRK16 Fab
    • Complex: Multidrug resistance protein 1
      • Protein or peptide: Multidrug resistance protein 1
    • Complex: MRK16 Fab-fragment light and heavy chain
      • Protein or peptide: MRK16 Fab-fragment light chain
      • Protein or peptide: MRK16 Fab-fragment heavy chain
  • Ligand: CHOLESTEROL

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Supramolecule #1: Nanodisc reconstituted, drug-free human ABCB1 in complex with MRK...

SupramoleculeName: Nanodisc reconstituted, drug-free human ABCB1 in complex with MRK16 Fab
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Molecular weightTheoretical: 240 KDa

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Supramolecule #2: Multidrug resistance protein 1

SupramoleculeName: Multidrug resistance protein 1 / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: MRK16 Fab-fragment light and heavy chain

SupramoleculeName: MRK16 Fab-fragment light and heavy chain / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2-#3
Source (natural)Organism: Mus musculus (house mouse)

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Macromolecule #1: Multidrug resistance protein 1

MacromoleculeName: Multidrug resistance protein 1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: ABC-type xenobiotic transporter
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 141.628781 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MDLEGDRNGG AKKKNFFKLN NKSEKDKKEK KPTVSVFSMF RYSNWLDKLY MVVGTLAAII HGAGLPLMML VFGEMTDIFA NAGNLEDLM SNITNRSDIN DTGFFMNLEE DMTRYAYYYS GIGAGVLVAA YIQVSFWCLA AGRQIHKIRK QFFHAIMRQE I GWFDVHDV ...String:
MDLEGDRNGG AKKKNFFKLN NKSEKDKKEK KPTVSVFSMF RYSNWLDKLY MVVGTLAAII HGAGLPLMML VFGEMTDIFA NAGNLEDLM SNITNRSDIN DTGFFMNLEE DMTRYAYYYS GIGAGVLVAA YIQVSFWCLA AGRQIHKIRK QFFHAIMRQE I GWFDVHDV GELNTRLTDD VSKINEGIGD KIGMFFQSMA TFFTGFIVGF TRGWKLTLVI LAISPVLGLS AAVWAKILSS FT DKELLAY AKAGAVAEEV LAAIRTVIAF GGQKKELERY NKNLEEAKRI GIKKAITANI SIGAAFLLIY ASYALAFWYG TTL VLSGEY SIGQVLTVFF SVLIGAFSVG QASPSIEAFA NARGAAYEIF KIIDNKPSID SYSKSGHKPD NIKGNLEFRN VHFS YPSRK EVKILKGLNL KVQSGQTVAL VGNSGCGKST TVQLMQRLYD PTEGMVSVDG QDIRTINVRF LREIIGVVSQ EPVLF ATTI AENIRYGREN VTMDEIEKAV KEANAYDFIM KLPHKFDTLV GERGAQLSGG QKQRIAIARA LVRNPKILLL DEATSA LDT ESEAVVQVAL DKARKGRTTI VIAHRLSTVR NADVIAGFDD GVIVEKGNHD ELMKEKGIYF KLVTMQTAGN EVELENA AD ESKSEIDALE MSSNDSRSSL IRKRSTRRSV RGSQAQDRKL STKEALDESI PPVSFWRIMK LNLTEWPYFV VGVFCAII N GGLQPAFAII FSKIIGVFTR IDDPETKRQN SNLFSLLFLA LGIISFITFF LQGFTFGKAG EILTKRLRYM VFRSMLRQD VSWFDDPKNT TGALTTRLAN DAAQVKGAIG SRLAVITQNI ANLGTGIIIS FIYGWQLTLL LLAIVPIIAI AGVVEMKMLS GQALKDKKE LEGAGKIATE AIENFRTVVS LTQEQKFEHM YAQSLQVPYR NSLRKAHIFG ITFSFTQAMM YFSYAGCFRF G AYLVAHKL MSFEDVLLVF SAVVFGAMAV GQVSSFAPDY AKAKISAAHI IMIIEKTPLI DSYSTEGLMP NTLEGNVTFG EV VFNYPTR PDIPVLQGLS LEVKKGQTLA LVGSSGCGKS TVVQLLERFY DPLAGKVLLD GKEIKRLNVQ WLRAHLGIVS QEP ILFDCS IAENIAYGDN SRVVSQEEIV RAAKEANIHA FIESLPNKYS TKVGDKGTQL SGGQKQRIAI ARALVRQPHI LLLD EATSA LDTESEKVVQ EALDKAREGR TCIVIAHRLS TIQNADLIVV FQNGRVKEHG THQQLLAQKG IYFSMVSVQA GTKRQ

UniProtKB: ATP-dependent translocase ABCB1

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Macromolecule #2: MRK16 Fab-fragment light chain

MacromoleculeName: MRK16 Fab-fragment light chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 24.139758 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: DVLMTQTPVS LSVSLGDQAS ISCRSSQSIV HSTGNTYLEW YLQKPGQSPK LLIYKISNRF SGVPDRFSGS GSGTDFTLKI SRVEAEDLG VYYCFQASHA PRTFGGGTKL EIKRADAAPT VSIFPPSSEQ LTSGGASVVC FLNNFYPKDI NVKWKIDGSE R QNGVLNSW ...String:
DVLMTQTPVS LSVSLGDQAS ISCRSSQSIV HSTGNTYLEW YLQKPGQSPK LLIYKISNRF SGVPDRFSGS GSGTDFTLKI SRVEAEDLG VYYCFQASHA PRTFGGGTKL EIKRADAAPT VSIFPPSSEQ LTSGGASVVC FLNNFYPKDI NVKWKIDGSE R QNGVLNSW TDQDSKDSTY SMSSTLTLTK DEYERHNSYT CEATHKTSTS PIVKSFNRNE C

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Macromolecule #3: MRK16 Fab-fragment heavy chain

MacromoleculeName: MRK16 Fab-fragment heavy chain / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 23.415236 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: EVILVESGGG LVKPGGSLKL SCAASGFTFS SYTMSWVRQT PEKRLEWVAT ISSGGGNTYY PDSVKGRFTI SRDNAKNNLY LQMSSLRSE DTALYYCARY YRYEAWFASW GQGTLVTVSA AKTTAPSVYP LAPVCGDTTG SSVTLGCLVK GYFPEPVTLT W NSGSLSSG ...String:
EVILVESGGG LVKPGGSLKL SCAASGFTFS SYTMSWVRQT PEKRLEWVAT ISSGGGNTYY PDSVKGRFTI SRDNAKNNLY LQMSSLRSE DTALYYCARY YRYEAWFASW GQGTLVTVSA AKTTAPSVYP LAPVCGDTTG SSVTLGCLVK GYFPEPVTLT W NSGSLSSG VHTFPAVLQS DLYTLSSSVT VTSSTWPSQS ITCNVAHPAS STKVDKKIEP

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Macromolecule #4: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 4 / Number of copies: 6 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL

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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

Concentration0.3 mg/mL
BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Average electron dose: 32.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 100.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.9 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 115341
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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