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- EMDB-4536: Nanodisc reconstituted Human-mouse chimeric ABCB1 (ABCB1HM)-EQ mu... -

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Basic information

Entry
Database: EMDB / ID: EMD-4536
TitleNanodisc reconstituted Human-mouse chimeric ABCB1 (ABCB1HM)-EQ mutant in complex with UIC2 Fab and Zosuquidar.
Map dataPostprocessed map of human-mouse chimeric ABCB1 (ABCB1HM)- EQ mutant in complex with UIC2 fab and zosuquidar
Sample
  • Complex: Nanodisc reconstituted ABCB1HM (human mouse chimeric ABCB1) EQ mutant in complex with UIC2 Fab and zosuquidar
    • Complex: ABCB1HM
      • Protein or peptide: ABCB1HM-EQ
    • Complex: UIC2 Fab
      • Protein or peptide: UIC2 Antigen Binding Fragment Light chain
      • Protein or peptide: UIC2 Antigen Binding Fragment Heavy Chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: Zosuquidar
  • Ligand: CHOLESTEROL
  • Ligand: 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOETHANOLAMINE
Biological speciesHomo sapiens (human) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.9 Å
AuthorsAlam A
Funding support Switzerland, 2 items
OrganizationGrant numberCountry
Swiss National Science Foundation Switzerland
European Molecular Biology Organization Switzerland
CitationJournal: Science / Year: 2019
Title: Structural insight into substrate and inhibitor discrimination by human P-glycoprotein.
Authors: Amer Alam / Julia Kowal / Eugenia Broude / Igor Roninson / Kaspar P Locher /
Abstract: ABCB1, also known as P-glycoprotein, actively extrudes xenobiotic compounds across the plasma membrane of diverse cells, which contributes to cellular drug resistance and interferes with therapeutic ...ABCB1, also known as P-glycoprotein, actively extrudes xenobiotic compounds across the plasma membrane of diverse cells, which contributes to cellular drug resistance and interferes with therapeutic drug delivery. We determined the 3.5-angstrom cryo-electron microscopy structure of substrate-bound human ABCB1 reconstituted in lipidic nanodiscs, revealing a single molecule of the chemotherapeutic compound paclitaxel (Taxol) bound in a central, occluded pocket. A second structure of inhibited, human-mouse chimeric ABCB1 revealed two molecules of zosuquidar occupying the same drug-binding pocket. Minor structural differences between substrate- and inhibitor-bound ABCB1 sites are amplified toward the nucleotide-binding domains (NBDs), revealing how the plasticity of the drug-binding site controls the dynamics of the adenosine triphosphate-hydrolyzing NBDs. Ordered cholesterol and phospholipid molecules suggest how the membrane modulates the conformational changes associated with drug binding and transport.
History
DepositionJan 7, 2019-
Header (metadata) releaseFeb 27, 2019-
Map releaseFeb 27, 2019-
UpdateJun 2, 2021-
Current statusJun 2, 2021Processing site: PDBe / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.025
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by height
  • Surface level: 0.025
  • Imaged by UCSF Chimera
  • Download
  • Surface view with fitted model
  • Atomic models: PDB-6qee
  • Surface level: 0.025
  • Imaged by UCSF Chimera
  • Download
Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_4536.png

Downloads & links

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Map

FileDownload / File: emd_4536.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationPostprocessed map of human-mouse chimeric ABCB1 (ABCB1HM)- EQ mutant in complex with UIC2 fab and zosuquidar
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.84 Å/pix.
x 400 pix.
= 336. Å		0.84 Å/pix.
x 400 pix.
= 336. Å		0.84 Å/pix.
x 400 pix.
= 336. 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: 0.02 / Movie #1: 0.025
Minimum - Maximum-0.078506015 - 0.17117816
Average (Standard dev.)7.188726e-05 (±0.0036248695)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 336.0 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.840.840.84
M x/y/z400400400
origin x/y/z0.0000.0000.000
length x/y/z336.000336.000336.000
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ364364364
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS400400400
D min/max/mean-0.0790.1710.000

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Supplemental data

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Sample components

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Entire : Nanodisc reconstituted ABCB1HM (human mouse chimeric ABCB1) EQ mu...

EntireName: Nanodisc reconstituted ABCB1HM (human mouse chimeric ABCB1) EQ mutant in complex with UIC2 Fab and zosuquidar
Components
  • Complex: Nanodisc reconstituted ABCB1HM (human mouse chimeric ABCB1) EQ mutant in complex with UIC2 Fab and zosuquidar
    • Complex: ABCB1HM
      • Protein or peptide: ABCB1HM-EQ
    • Complex: UIC2 Fab
      • Protein or peptide: UIC2 Antigen Binding Fragment Light chain
      • Protein or peptide: UIC2 Antigen Binding Fragment Heavy Chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: Zosuquidar
  • Ligand: CHOLESTEROL
  • Ligand: 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOETHANOLAMINE

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Supramolecule #1: Nanodisc reconstituted ABCB1HM (human mouse chimeric ABCB1) EQ mu...

SupramoleculeName: Nanodisc reconstituted ABCB1HM (human mouse chimeric ABCB1) EQ mutant in complex with UIC2 Fab and zosuquidar
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Molecular weightExperimental: 200 KDa

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Supramolecule #2: ABCB1HM

SupramoleculeName: ABCB1HM / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human)

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Supramolecule #3: UIC2 Fab

SupramoleculeName: UIC2 Fab / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2-#3
Source (natural)Organism: Mus musculus (house mouse)
Recombinant expressionOrganism: Mus musculus (house mouse)

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Macromolecule #1: ABCB1HM-EQ

MacromoleculeName: ABCB1HM-EQ / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 143.627828 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MELEEDLKGR ADKNFSKMGK KSKKEKKEKK PAVSVLTMFR YAGWLDRLYM LVGTLAAIIH GVALPLMMLI FGEMTDIFAN AGNLEDLMS NITNRSDIND TGFFMNLEED MTTYAYYYTG IGAGVLIVAY IQVSFWCLAA GRQIHKIRQK FFHAIMNQEI G WFDVHDVG ...String:
MELEEDLKGR ADKNFSKMGK KSKKEKKEKK PAVSVLTMFR YAGWLDRLYM LVGTLAAIIH GVALPLMMLI FGEMTDIFAN AGNLEDLMS NITNRSDIND TGFFMNLEED MTTYAYYYTG IGAGVLIVAY IQVSFWCLAA GRQIHKIRQK FFHAIMNQEI G WFDVHDVG ELNTRLTDDV SKINEGIGDK IGMFFQAMAT FFGGFIIGFT RGWKLTLVIL AISPVLGLSA GIWAKILSSF TD KELHAYA KAGAVAEEVL AAIRTVIAFG GQKKELERYN NNLEEAKRLG IKKAITANIS MGAAFLLIYA SYALAFWYGT TLV LSGEYS IGQVLTVFFS VLIGAFSVGQ ASPNIEAFAN ARGAAYEVFK IIDNKPSIDS FSKSGHKPDN IQGNLEFKNI HFSY PSRKE VQILKGLNLK VKSGQTVALV GNSGCGKSTT VQLMQRLYDP LDGMVSIDGQ DIRTINVRYL REIIGVVSQE PVLFA TTIA ENIRYGREDV TMDEIEKAVK EANAYDFIMK LPHQFDTLVG ERGAQLSGGQ KQRIAIARAL VRNPKILLLD QATSAL DTE SEAVVQAALD KAREGRTTIV IAHRLSTVRN ADVIAGFDGG VIVEQGNHDE LMREKGIYFK LVMTQTAGNE IELGNEA CK SKDEIDNLDM SSKDSGSSLI RRRSTRKSIC GPHDQDRKLS TKEALDEDVP PASFWRILKL NSTEWPYFVV GIFCAIIN G GLQPAFSVIF SKIIGVFTRI DDPETKRQNS NLFSLLFLIL GIISFITFFL QGFTFGKAGE ILTKRLRYMV FKSMLRQDV SWFDDPKNTT GALTTRLAND AAQVKGATGS RLAVIFQNIA NLGTGIIISF IYGWQLTLLL LAIVPIIAIA GVVEMKMLSG QALKDKKEL EGSGKIATEA IENFRTVVSL TREQKFETMY AQSLQIPYRN AMKKAHVFGI TFSFTQAMMY FSYAACFRFG A YLVAHKLM SFEDVLLVFS AIVFGAMAVG QVSSFAPDYA KATVSASHII RIIEKTPEID SYSTQGLKPN MLEGNVQFSG VV FNYPTRP SIPVLQGLSL EVKKGQTLAL VGSSGCGKST VVQLLERFYD PMAGSVFLDG KEIKQLNVQW LRAQLGIVSQ EPI LFDCSI AENIAYGDNS RVVSYEEIVR AAKEANIHQF IDSLPDKYNT RVGDKGTQLS GGQKQRIAIA RALVRQPHIL LLDQ ATSAL DTESEKVVQE ALDKAREGRT CIVIAHRLST IQNADLIVVI QNGKVKEHGT HQQLLAQKGI YFSMVSVQAG AKRSS GAGG EFLELSRVDA LEVLFQ

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Macromolecule #2: UIC2 Antigen Binding Fragment Light chain

MacromoleculeName: UIC2 Antigen Binding Fragment Light chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 24.321039 KDa
Recombinant expressionOrganism: Mus musculus (house mouse)
SequenceString: QVVMTQSPLS LPVSLGDQAS ISCRSSQSLL HSNGNTYLHW YLQKPGQSPK LLIYKVSNRF SGVPDRFSGS GSGTDFTLKI SRVEAEDLG VYFCSQSTHI PPWTFGGGTK LDIKRADAAP TVSIFPPSSE QLTSGGLSVV CFLNNFYPKD INVKWKIDGS E RQNGVLNS ...String:
QVVMTQSPLS LPVSLGDQAS ISCRSSQSLL HSNGNTYLHW YLQKPGQSPK LLIYKVSNRF SGVPDRFSGS GSGTDFTLKI SRVEAEDLG VYFCSQSTHI PPWTFGGGTK LDIKRADAAP TVSIFPPSSE QLTSGGLSVV CFLNNFYPKD INVKWKIDGS E RQNGVLNS WTDQDSKDST YSMSSTLTLT KDEYERHNSY TCEATHKTST SPIVKSFNRN EC

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Macromolecule #3: UIC2 Antigen Binding Fragment Heavy Chain

MacromoleculeName: UIC2 Antigen Binding Fragment Heavy Chain / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 24.381281 KDa
Recombinant expressionOrganism: Mus musculus (house mouse)
SequenceString: EVQLQESGPE LVKTGASVKI SCKASGYSFS NYYIHWVKQS HGKSLEWIGF ISCYNGATFY NQKFKGKATF TVDNSSSTAY MKFNSLTFE DSAVYYCARL PIQFGNFYPM DYWGQGTTVT VSSAKTTAPS VYPLAPVCGD TTGSSVTLGC LVKGYFPEPV T LTWNSGSL ...String:
EVQLQESGPE LVKTGASVKI SCKASGYSFS NYYIHWVKQS HGKSLEWIGF ISCYNGATFY NQKFKGKATF TVDNSSSTAY MKFNSLTFE DSAVYYCARL PIQFGNFYPM DYWGQGTTVT VSSAKTTAPS VYPLAPVCGD TTGSSVTLGC LVKGYFPEPV T LTWNSGSL SSGVHTFPAV LQSDLYTLSS SVTVTSSTWP SQSITCNVAH PASSTKVDKK IEPRGPT

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Macromolecule #4: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 4 / Number of copies: 3 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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Macromolecule #5: Zosuquidar

MacromoleculeName: Zosuquidar / type: ligand / ID: 5 / Number of copies: 2 / Formula: ZQU
Molecular weightTheoretical: 527.604 Da
Chemical component information

ChemComp-ZQU:
Zosuquidar / antineoplastic*YM

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Macromolecule #6: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 6 / Number of copies: 7 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL

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Macromolecule #7: 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOETHANOLAMINE

MacromoleculeName: 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOETHANOLAMINE / type: ligand / ID: 7 / Number of copies: 1 / Formula: 3PE
Molecular weightTheoretical: 748.065 Da

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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

Concentration0.2 mg/mL
BufferpH: 7.5
GridModel: Quantifoil R1.2/1.3 / Material: COPPER
VitrificationCryogen name: ETHANE-PROPANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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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: 2.1 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

6fn1

Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.9 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 291197
Initial angle assignmentType: PROJECTION MATCHING
Final angle assignmentType: PROJECTION MATCHING
FSC plot (resolution estimation)

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