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- EMDB-4282: Apo form of UIC2 Fab complex of human-mouse chimeric ABCB1 (ABCB1HM) -

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Basic information

Entry
Database: EMDB / ID: EMD-4282
TitleApo form of UIC2 Fab complex of human-mouse chimeric ABCB1 (ABCB1HM)
Map dataHuman-mouse chimeric ABCB1 (ABCB1Hm) complex with UIC2 Antigen binding fragment
Sample
  • Complex: Apo Human-mouse chimeric ABCB1 (ABCB1HM) complex with UIC2 fab
    • Complex: Apo Human-mouse chimeric ABCB1 (ABCB1HM) complex with UIC2 fab
      • Protein or peptide: Apo form of Human-mouse chimeric ABCB1 (ABCB1HM) in complex with Antigen binding fragment of UIC2.
    • Complex: Apo Human-mouse chimeric ABCB1 (ABCB1HM) complex with 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: 1,2-Distearoyl-sn-glycerophosphoethanolamine
KeywordsMembrane Transport Protein ABCB1 ABC Exporter Small molecule inhibitor Antibody complex / MEMBRANE PROTEIN
Function / homology
Function and homology information


positive regulation of anion channel activity / carboxylic acid transmembrane transport / carboxylic acid transmembrane transporter activity / terpenoid transport / ceramide floppase activity / regulation of response to osmotic stress / floppase activity / ceramide translocation / Abacavir transmembrane transport / external side of apical plasma membrane ...positive regulation of anion channel activity / carboxylic acid transmembrane transport / carboxylic acid transmembrane transporter activity / terpenoid transport / ceramide floppase activity / regulation of response to osmotic stress / floppase activity / ceramide translocation / Abacavir transmembrane transport / external side of apical plasma membrane / Atorvastatin ADME / phosphatidylethanolamine flippase activity / xenobiotic transport across blood-brain barrier / transepithelial transport / phosphatidylcholine floppase activity / xenobiotic detoxification by transmembrane export across the plasma membrane / export across plasma membrane / ABC-type xenobiotic transporter / P-type phospholipid transporter / ABC-type xenobiotic transporter activity / phospholipid translocation / Prednisone ADME / efflux transmembrane transporter activity / xenobiotic transmembrane transporter activity / transmembrane transporter activity / ATPase-coupled transmembrane transporter activity / transport across blood-brain barrier / xenobiotic metabolic process / regulation of chloride transport / stem cell proliferation / ABC-family proteins mediated transport / transmembrane transport / G2/M transition of mitotic cell cycle / response to xenobiotic stimulus / apical plasma membrane / 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: 4.14 Å
AuthorsAlam A / Locher KP
Funding support Switzerland, United States, 3 items
OrganizationGrant numberCountry
Swiss National Science Foundation Switzerland
European Molecular Biology Organization Switzerland
National Institutes of Health United States
CitationJournal: Proc Natl Acad Sci U S A / Year: 2018
Title: Structure of a zosuquidar and UIC2-bound human-mouse chimeric ABCB1.
Authors: Amer Alam / Raphael Küng / Julia Kowal / Robert A McLeod / Nina Tremp / Eugenia V Broude / Igor B Roninson / Henning Stahlberg / Kaspar P Locher /
Abstract: The multidrug transporter ABCB1 (P-glycoprotein) is an ATP-binding cassette transporter that has a key role in protecting tissues from toxic insult and contributes to multidrug extrusion from cancer ...The multidrug transporter ABCB1 (P-glycoprotein) is an ATP-binding cassette transporter that has a key role in protecting tissues from toxic insult and contributes to multidrug extrusion from cancer cells. Here, we report the near-atomic resolution cryo-EM structure of nucleotide-free ABCB1 trapped by an engineered disulfide cross-link between the nucleotide-binding domains (NBDs) and bound to the antigen-binding fragment of the human-specific inhibitory antibody UIC2 and to the third-generation ABCB1 inhibitor zosuquidar. Our structure reveals the transporter in an occluded conformation with a central, enclosed, inhibitor-binding pocket lined by residues from all transmembrane (TM) helices of ABCB1. The pocket spans almost the entire width of the lipid membrane and is occupied exclusively by two closely interacting zosuquidar molecules. The external, conformational epitope facilitating UIC2 binding is also visualized, providing a basis for its inhibition of substrate efflux. Additional cryo-EM structures suggest concerted movement of TM helices from both halves of the transporters associated with closing the NBD gap, as well as zosuquidar binding. Our results define distinct recognition interfaces of ABCB1 inhibitory agents, which may be exploited for therapeutic purposes.
History
DepositionFeb 2, 2018-
Header (metadata) releaseFeb 14, 2018-
Map releaseFeb 21, 2018-
UpdateOct 16, 2024-
Current statusOct 16, 2024Processing site: PDBe / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.07
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 0.07
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  • Surface view with fitted model
  • Atomic models: PDB-6fn4
  • Surface level: 0.07
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_4282.png

Downloads & links

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Map

FileDownload / File: emd_4282.map.gz / Format: CCP4 / Size: 30.5 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationHuman-mouse chimeric ABCB1 (ABCB1Hm) complex with UIC2 Antigen binding fragment
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.39 Å/pix.
x 200 pix.
= 277.4 Å		1.39 Å/pix.
x 200 pix.
= 277.4 Å		1.39 Å/pix.
x 200 pix.
= 277.4 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.387 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.07 / Movie #1: 0.07
Minimum - Maximum-0.464311 - 0.68975216
Average (Standard dev.)0.00016140916 (±0.015309235)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions200200200
Spacing200200200
CellA=B=C: 277.4 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.3871.3871.387
M x/y/z200200200
origin x/y/z0.0000.0000.000
length x/y/z277.400277.400277.400
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS200200200
D min/max/mean-0.4640.6900.000

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Supplemental data

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Sample components

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Entire : Apo Human-mouse chimeric ABCB1 (ABCB1HM) complex with UIC2 fab

EntireName: Apo Human-mouse chimeric ABCB1 (ABCB1HM) complex with UIC2 fab
Components
  • Complex: Apo Human-mouse chimeric ABCB1 (ABCB1HM) complex with UIC2 fab
    • Complex: Apo Human-mouse chimeric ABCB1 (ABCB1HM) complex with UIC2 fab
      • Protein or peptide: Apo form of Human-mouse chimeric ABCB1 (ABCB1HM) in complex with Antigen binding fragment of UIC2.
    • Complex: Apo Human-mouse chimeric ABCB1 (ABCB1HM) complex with 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: 1,2-Distearoyl-sn-glycerophosphoethanolamine

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Supramolecule #1: Apo Human-mouse chimeric ABCB1 (ABCB1HM) complex with UIC2 fab

SupramoleculeName: Apo Human-mouse chimeric ABCB1 (ABCB1HM) complex with UIC2 fab
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Molecular weightTheoretical: 195 KDa

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Supramolecule #2: Apo Human-mouse chimeric ABCB1 (ABCB1HM) complex with UIC2 fab

SupramoleculeName: Apo Human-mouse chimeric ABCB1 (ABCB1HM) complex with UIC2 fab
type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 142 KDa

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Supramolecule #3: Apo Human-mouse chimeric ABCB1 (ABCB1HM) complex with UIC2 fab

SupramoleculeName: Apo Human-mouse chimeric ABCB1 (ABCB1HM) complex with UIC2 fab
type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2-#3
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 48.7 KDa

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Macromolecule #1: Apo form of Human-mouse chimeric ABCB1 (ABCB1HM) in complex with ...

MacromoleculeName: Apo form of Human-mouse chimeric ABCB1 (ABCB1HM) in complex with Antigen binding fragment of UIC2.
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 141.283156 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MELEEDLKGR ADKNFSKMGK KSKKEKKEKK PAVSVLTMFR YAGWLDRLYM LVGTLAAIIH GVALPLMMLI FGEMTDIFAN AGNLEDLMS NITNRSDIND TGFFMNLEED MTTYAYYYTG IGAGVLIVAY IQVSFWLLAA GRQIHKIRQK FFHAIMNQEI G WFDVHDVG ...String:
MELEEDLKGR ADKNFSKMGK KSKKEKKEKK PAVSVLTMFR YAGWLDRLYM LVGTLAAIIH GVALPLMMLI FGEMTDIFAN AGNLEDLMS NITNRSDIND TGFFMNLEED MTTYAYYYTG IGAGVLIVAY IQVSFWLLAA 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 GNSGAGKSTT VQLMQRLYDP LDGMVSIDGQ DIRTINVRYL REIIGVVSQE PVLFA TTIA ENIRYGREDV TMDEIEKAVK EANAYDFIMK LPHQFDTLVG ERGAQLSGGQ KQRIAIARAL VRNPKILLLD EATCAL DTE SEAVVQAALD KAREGRTTIV IAHRLSTVRN ADVIAGFDGG VIVEQGNHDE LMREKGIYFK LVMTQTAGNE IELGNEA AK SKDEIDNLDM SSKDSGSSLI RRRSTRKSIA GPHDQDRKLS TKEALDEDVP PASFWRILKL NSTEWPYFVV GIFVAIIN G GLQPAFSVIF SKIIGVFTRI DDPETKRQNS NLFSLLFLIL GIISFITFFL QGFTFGKAGE ILTKRLRYMV FKSMLRQDV SWFDDPKNTT GALTTRLAND AAQVKGATGS RLAVIFQNIA NLGTGIIISF IYGWQLTLLL LAIVPIIAIA GVVEMKMLSG QALKDKKEL EGSGKIATEA IENFRTVVSL TREQKFETMY AQSLQIPYRN AMKKAHVFGI TFSFTQAMMY FSYAAAFRFG A YLVAHKLM SFEDVLLVFS AIVFGAMAVG QVSSFAPDYA KATVSASHII RIIEKTPEID SYSTQGLKPN MLEGNVQFSG VV FNYPTRP SIPVLQGLSL EVKKGQTLAL VGSSGAGKST VVQLLERFYD PMAGSVFLDG KEIKQLNVQW LRAQLGIVSQ EPI LFDTSI AENIAYGDNS RVVSYEEIVR AAKEANIHQF IDSLPDKYNT RVGDKGTQLS GGQKQRIAIA RALVRQPHIL LLDE ATCAL DTESEKVVQE ALDKAREGRT TIVIAHRLST IQNADLIVVI QNGKVKEHGT HQQLLAQKGI YFSMVSVQAG AKRS

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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: 1,2-Distearoyl-sn-glycerophosphoethanolamine

MacromoleculeName: 1,2-Distearoyl-sn-glycerophosphoethanolamine / type: ligand / ID: 5 / Number of copies: 1 / Formula: 3PE
Molecular weightTheoretical: 748.065 Da
Chemical component information

ChemComp-3PE:
1,2-Distearoyl-sn-glycerophosphoethanolamine / phospholipid*YM

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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

BufferpH: 7.5
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: 0.9 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: OTHER
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 4.14 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 517053
Initial angle assignmentType: PROJECTION MATCHING
Final angle assignmentType: PROJECTION MATCHING

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