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- EMDB-4281: Zosuquidar and UIC2 Fab complex of human-mouse chimeric ABCB1 (AB... -

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Basic information

Entry
Database: EMDB / ID: EMD-4281
TitleZosuquidar and UIC2 Fab complex of human-mouse chimeric ABCB1 (ABCB1HM)
Map dataZosuquidar complex of ABCB1HM-X. Final post-processed map after partial detergent belt removal.
Sample
  • Complex: Human-mouse chimeric ABCB1 (ABCB1HM) complex with UIC2 fab and zosuquidar
    • Complex: Human-mouse chimeric ABCB1 (ABCB1HM) complex with UIC2 fab and zosuquidar
      • Protein or peptide: Human-mouse chimeric ABCB1 (ABCBHM)
    • Complex: Human-mouse chimeric ABCB1 (ABCB1HM) complex with UIC2 fab and zosuquidar
      • 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
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 / Abacavir transmembrane transport / ceramide translocation / 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 / Abacavir transmembrane transport / ceramide translocation / 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: 3.58 Å
AuthorsAlam A / Locher KP
Funding support Switzerland, United States, 3 items
OrganizationGrant numberCountry
Swiss National Science Foundation Switzerland
National Institutes of Health United States
European Molecular Biology Organization Switzerland
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 21, 2018-
Map releaseFeb 21, 2018-
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: 0.025
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 0.025
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6fn1
  • Surface level: 0.025
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_4281.png

Downloads & links

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Map

FileDownload / File: emd_4281.map.gz / Format: CCP4 / Size: 163.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationZosuquidar complex of ABCB1HM-X. Final post-processed map after partial detergent belt removal.
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.84 Å/pix.
x 350 pix.
= 294. Å		0.84 Å/pix.
x 350 pix.
= 294. Å		0.84 Å/pix.
x 350 pix.
= 294. 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: 0.025 / Movie #1: 0.025
Minimum - Maximum-0.13838151 - 0.22620861
Average (Standard dev.)-0.00004454797 (±0.004538118)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions350350350
Spacing350350350
CellA=B=C: 294.0 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.840.840.84
M x/y/z350350350
origin x/y/z0.0000.0000.000
length x/y/z294.000294.000294.000
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS350350350
D min/max/mean-0.1380.226-0.000

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Supplemental data

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Sample components

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Entire : Human-mouse chimeric ABCB1 (ABCB1HM) complex with UIC2 fab and zo...

EntireName: Human-mouse chimeric ABCB1 (ABCB1HM) complex with UIC2 fab and zosuquidar
Components
  • Complex: Human-mouse chimeric ABCB1 (ABCB1HM) complex with UIC2 fab and zosuquidar
    • Complex: Human-mouse chimeric ABCB1 (ABCB1HM) complex with UIC2 fab and zosuquidar
      • Protein or peptide: Human-mouse chimeric ABCB1 (ABCBHM)
    • Complex: Human-mouse chimeric ABCB1 (ABCB1HM) complex with UIC2 fab and zosuquidar
      • 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

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

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

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

SupramoleculeName: Human-mouse chimeric ABCB1 (ABCB1HM) complex with UIC2 fab and zosuquidar
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: Human-mouse chimeric ABCB1 (ABCB1HM) complex with UIC2 fab and zo...

SupramoleculeName: Human-mouse chimeric ABCB1 (ABCB1HM) complex with UIC2 fab and zosuquidar
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: Human-mouse chimeric ABCB1 (ABCBHM)

MacromoleculeName: Human-mouse chimeric ABCB1 (ABCBHM) / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 137.719953 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: PAVSVLTMFR YAGWLDRLYM LVGTLAAIIH GVALPLMMLI FGEMTDIFAN AGNLEDLMSN ITNRSDINDT GFFMNLEEDM TTYAYYYTG IGAGVLIVAY IQVSFWLLAA GRQIHKIRQK FFHAIMNQEI GWFDVHDVGE LNTRLTDDVS KINEGIGDKI G MFFQAMAT ...String:
PAVSVLTMFR YAGWLDRLYM LVGTLAAIIH GVALPLMMLI FGEMTDIFAN AGNLEDLMSN ITNRSDINDT GFFMNLEEDM TTYAYYYTG IGAGVLIVAY IQVSFWLLAA GRQIHKIRQK FFHAIMNQEI GWFDVHDVGE LNTRLTDDVS KINEGIGDKI G MFFQAMAT FFGGFIIGFT RGWKLTLVIL AISPVLGLSA GIWAKILSSF TDKELHAYAK AGAVAEEVLA AIRTVIAFGG QK KELERYN NNLEEAKRLG IKKAITANIS MGAAFLLIYA SYALAFWYGT TLVLSGEYSI GQVLTVFFSV LIGAFSVGQA SPN IEAFAN ARGAAYEVFK IIDNKPSIDS FSKSGHKPDN IQGNLEFKNI HFSYPSRKEV QILKGLNLKV KSGQTVALVG NSGA GKSTT VQLMQRLYDP LDGMVSIDGQ DIRTINVRYL REIIGVVSQE PVLFATTIAE NIRYGREDVT MDEIEKAVKE ANAYD FIMK LPHQFDTLVG ERGAQLSGGQ KQRIAIARAL VRNPKILLLD EATCALDTES EAVVQAALDK AREGRTTIVI AHRLST VRN ADVIAGFDGG VIVEQGNHDE LMREKGIYFK LVMTQTAGNE IELGNEAAKS KDEIDNLDMS SKDSGSSLIR RRSTRKS IA GPHDQDRKLS TKEALDEDVP PASFWRILKL NSTEWPYFVV GIFVAIINGG LQPAFSVIFS KIIGVFTRID DPETKRQN S NLFSLLFLIL GIISFITFFL QGFTFGKAGE ILTKRLRYMV FKSMLRQDVS WFDDPKNTTG ALTTRLANDA AQVKGATGS RLAVIFQNIA NLGTGIIISF IYGWQLTLLL LAIVPIIAIA GVVEMKMLSG QALKDKKELE GSGKIATEAI ENFRTVVSLT REQKFETMY AQSLQIPYRN AMKKAHVFGI TFSFTQAMMY FSYAAAFRFG AYLVAHKLMS FEDVLLVFSA IVFGAMAVGQ V SSFAPDYA KATVSASHII RIIEKTPEID SYSTQGLKPN MLEGNVQFSG VVFNYPTRPS IPVLQGLSLE VKKGQTLALV GS SGAGKST VVQLLERFYD PMAGSVFLDG KEIKQLNVQW LRAQLGIVSQ EPILFDTSIA ENIAYGDNSR VVSYEEIVRA AKE ANIHQF IDSLPDKYNT RVGDKGTQLS GGQKQRIAIA RALVRQPHIL LLDEATCALD TESEKVVQEA LDKAREGRTT IVIA HRLST 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: 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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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: 1.54 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

Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.58 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 231969
Initial angle assignmentType: PROJECTION MATCHING
Final angle assignmentType: PROJECTION MATCHING

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