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- EMDB-3654: Structure of an ABC transporter -

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Basic information

Entry
Database: EMDB / ID: EMD-3654
TitleStructure of an ABC transporter
Map dataMap after post-processing and masking
Sample
  • Complex: Nanodisc-reconstituted ABCG2 in complex with 5D3-Fab
    • Complex: Nanodisc-reconstituted ABCG2
      • Protein or peptide: ATP-binding cassette sub-family G member 2
    • Complex: 5D3-Fab
      • Protein or peptide: 5D3-Fab heavy chain
      • Protein or peptide: 5D3-Fab light chain
Function / homology
Function and homology information


biotin transmembrane transporter activity / biotin transport / riboflavin transport / riboflavin transmembrane transporter activity / renal urate salt excretion / urate metabolic process / urate transmembrane transporter activity / Abacavir transmembrane transport / organic anion transport / external side of apical plasma membrane ...biotin transmembrane transporter activity / biotin transport / riboflavin transport / riboflavin transmembrane transporter activity / renal urate salt excretion / urate metabolic process / urate transmembrane transporter activity / Abacavir transmembrane transport / organic anion transport / external side of apical plasma membrane / organic anion transmembrane transporter activity / xenobiotic transport across blood-brain barrier / export across plasma membrane / ABC-type xenobiotic transporter / Paracetamol ADME / Ciprofloxacin ADME / transepithelial transport / cellular detoxification / ABC-type xenobiotic transporter activity / NFE2L2 regulating MDR associated enzymes / Heme biosynthesis / Heme degradation / lipid transport / xenobiotic transmembrane transporter activity / efflux transmembrane transporter activity / transport across blood-brain barrier / ATPase-coupled transmembrane transporter activity / mitochondrial membrane / brush border membrane / Iron uptake and transport / transmembrane transport / membrane raft / apical plasma membrane / ATP hydrolysis activity / protein homodimerization activity / nucleoplasm / ATP binding / identical protein binding / plasma membrane
Similarity search - Function
ABC transporter family G domain / ABC-2 type transporter / ABC-2 type transporter / ABC-2 type transporter / 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
Broad substrate specificity ATP-binding cassette transporter ABCG2
Similarity search - Component
Biological speciesHomo sapiens (human) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.78 Å
AuthorsTaylor NMI / Manolaridis I / Jackson SM / Kowal J / Stahlberg H / Locher KP
Funding support Switzerland, 2 items
OrganizationGrant numberCountry
SNSF NCCR TransCure Switzerland
ETH ZurichETH-22-14-1
CitationJournal: Nature / Year: 2017
Title: Structure of the human multidrug transporter ABCG2.
Authors: Nicholas M I Taylor / Ioannis Manolaridis / Scott M Jackson / Julia Kowal / Henning Stahlberg / Kaspar P Locher /
Abstract: ABCG2 is a constitutively expressed ATP-binding cassette (ABC) transporter that protects many tissues against xenobiotic molecules. Its activity affects the pharmacokinetics of commonly used drugs ...ABCG2 is a constitutively expressed ATP-binding cassette (ABC) transporter that protects many tissues against xenobiotic molecules. Its activity affects the pharmacokinetics of commonly used drugs and limits the delivery of therapeutics into tumour cells, thus contributing to multidrug resistance. Here we present the structure of human ABCG2 determined by cryo-electron microscopy, providing the first high-resolution insight into a human multidrug transporter. We visualize ABCG2 in complex with two antigen-binding fragments of the human-specific, inhibitory antibody 5D3 that recognizes extracellular loops of the transporter. We observe two cholesterol molecules bound in the multidrug-binding pocket that is located in a central, hydrophobic, inward-facing translocation pathway between the transmembrane domains. Combined with functional in vitro analyses, our results suggest a multidrug recognition and transport mechanism of ABCG2, rationalize disease-causing single nucleotide polymorphisms and the allosteric inhibition by the 5D3 antibody, and provide the structural basis of cholesterol recognition by other G-subfamily ABC transporters.
History
DepositionMar 28, 2017-
Header (metadata) releaseJun 7, 2017-
Map releaseJun 7, 2017-
UpdateJul 29, 2020-
Current statusJul 29, 2020Processing site: PDBe / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.038
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 0.038
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-5njg
  • Surface level: 0.038
  • Imaged by UCSF Chimera
  • Download
  • Surface view with fitted model
  • Atomic models: PDB-5nj3
  • Surface level: 0.038
  • Imaged by UCSF Chimera
  • Download
Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_3654.png

Downloads & links

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Map

FileDownload / File: emd_3654.map.gz / Format: CCP4 / Size: 52.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationMap after post-processing and masking
Voxel sizeX=Y=Z: 1.039 Å
Density
Contour LevelBy AUTHOR: 0.038 / Movie #1: 0.038
Minimum - Maximum-0.1701426 - 0.28731483
Average (Standard dev.)0.0012506316 (±0.008311617)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions240240240
Spacing240240240
CellA=B=C: 249.36002 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.0391.0391.039
M x/y/z240240240
origin x/y/z0.0000.0000.000
length x/y/z249.360249.360249.360
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS240240240
D min/max/mean-0.1700.2870.001

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Supplemental data

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Sample components

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Entire : Nanodisc-reconstituted ABCG2 in complex with 5D3-Fab

EntireName: Nanodisc-reconstituted ABCG2 in complex with 5D3-Fab
Components
  • Complex: Nanodisc-reconstituted ABCG2 in complex with 5D3-Fab
    • Complex: Nanodisc-reconstituted ABCG2
      • Protein or peptide: ATP-binding cassette sub-family G member 2
    • Complex: 5D3-Fab
      • Protein or peptide: 5D3-Fab heavy chain
      • Protein or peptide: 5D3-Fab light chain

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Supramolecule #1: Nanodisc-reconstituted ABCG2 in complex with 5D3-Fab

SupramoleculeName: Nanodisc-reconstituted ABCG2 in complex with 5D3-Fab / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all

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Supramolecule #2: Nanodisc-reconstituted ABCG2

SupramoleculeName: Nanodisc-reconstituted ABCG2 / 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: 5D3-Fab

SupramoleculeName: 5D3-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: ATP-binding cassette sub-family G member 2

MacromoleculeName: ATP-binding cassette sub-family G member 2 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 73.395742 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: DYKDDDDKGS SSSNVEVFIP VSQGNTNGFP ATASNDLKAF TEGAVLSFHN ICYRVKLKSG FLPCRKPVEK EILSNINGIM KPGLNAILG PTGGGKSSLL DVLAARKDPS GLSGDVLING APRPANFKCN SGYVVQDDVV MGTLTVRENL QFSAALRLAT T MTNHEKNE ...String:
DYKDDDDKGS SSSNVEVFIP VSQGNTNGFP ATASNDLKAF TEGAVLSFHN ICYRVKLKSG FLPCRKPVEK EILSNINGIM KPGLNAILG PTGGGKSSLL DVLAARKDPS GLSGDVLING APRPANFKCN SGYVVQDDVV MGTLTVRENL QFSAALRLAT T MTNHEKNE RINRVIQELG LDKVADSKVG TQFIRGVSGG ERKRTSIGME LITDPSILFL DEPTTGLDSS TANAVLLLLK RM SKQGRTI IFSIHQPRYS IFKLFDSLTL LASGRLMFHG PAQEALGYFE SAGYHCEAYN NPADFFLDII NGDSTAVALN REE DFKATE IIEPSKQDKP LIEKLAEIYV NSSFYKETKA ELHQLSGGEK KKKITVFKEI SYTTSFCHQL RWVSKRSFKN LLGN PQASI AQIIVTVVLG LVIGAIYFGL KNDSTGIQNR AGVLFFLTTN QCFSSVSAVE LFVVEKKLFI HEYISGYYRV SSYFL GKLL SDLLPMRMLP SIIFTCIVYF MLGLKPKADA FFVMMFTLMM VAYSASSMAL AIAAGQSVVS VATLLMTICF VFMMIF SGL LVNLTTIASW LSWLQYFSIP RYGFTALQHN EFLGQNFCPG LNATGNNPCN YATCTGEEYL VKQGIDLSPW GLWKNHV AL ACMIVIFLTI AYLKLLFLKK YS

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Macromolecule #2: 5D3-Fab heavy chain

MacromoleculeName: 5D3-Fab heavy chain / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 23.843633 KDa
Recombinant expressionOrganism: Mus musculus (house mouse)
SequenceString: QVQLQESGPG LVKPSQSLSL TCTVTGFSIT SDYAWNWIRQ FPGKKLEWMG YINFDGGTTY NPSLRGRISI TRDTSKNQFF LQLRSVTPE DTATYYCATF YGAKGTLDYW GQGTSVTVSS AKTTPPSVYP LAPVCGDTSG SSVTLGCLVK GYFPEPVTLT W NSGSLSSG ...String:
QVQLQESGPG LVKPSQSLSL TCTVTGFSIT SDYAWNWIRQ FPGKKLEWMG YINFDGGTTY NPSLRGRISI TRDTSKNQFF LQLRSVTPE DTATYYCATF YGAKGTLDYW GQGTSVTVSS AKTTPPSVYP LAPVCGDTSG SSVTLGCLVK GYFPEPVTLT W NSGSLSSG VHTFPAVLQS DLYTLSSSVT VTSSTWPSQS ITCNVAHPAS STKVDKKIEP RGP

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Macromolecule #3: 5D3-Fab light chain

MacromoleculeName: 5D3-Fab light chain / type: protein_or_peptide / ID: 3 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 23.594016 KDa
Recombinant expressionOrganism: Mus musculus (house mouse)
SequenceString: DIVLTQSPSS FSVSLGDRVT ISCKASGYIL NRLAWYQQKP GNAPRLLISG ATSLETGFPS RFSGTGSGKD YTLSISSLQT EDVGTYYCQ QYWSTPWTFG GGTKLEIRRA DAAPTVSIFP PSSEQLTSGG ASVVCFLNNF YPKDINVKWK IDGSERQNGV L NSWTDQDS ...String:
DIVLTQSPSS FSVSLGDRVT ISCKASGYIL NRLAWYQQKP GNAPRLLISG ATSLETGFPS RFSGTGSGKD YTLSISSLQT EDVGTYYCQ QYWSTPWTFG GGTKLEIRRA DAAPTVSIFP PSSEQLTSGG ASVVCFLNNF YPKDINVKWK IDGSERQNGV L NSWTDQDS KDSTYSMSST LTLTKDEYER HNSYTCEATH KTSTSPIVKS FNRNEC

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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
VitrificationCryogen name: ETHANE-PROPANE

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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
Specialist opticsEnergy filter - Name: GIF Quantum LS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Digitization - Frames/image: 1-40 / Average electron dose: 67.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionSoftware - Name: Gctf
Initial angle assignmentType: PROJECTION MATCHING / Software - Name: RELION
Final angle assignmentType: PROJECTION MATCHING / Software - Name: RELION
Final reconstructionApplied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 3.78 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Number images used: 97612
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL
Output model

PDB-5nj3:
Structure of an ABC transporter: complete structure

PDB-5njg:
Structure of an ABC transporter: part of the structure that could be built de novo

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