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- EMDB-14760: ABCB1 V978C mutant (mABCB1) in the outward facing state bound to AAC -

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Basic information

Entry
Database: EMDB / ID: EMD-14760
TitleABCB1 V978C mutant (mABCB1) in the outward facing state bound to AAC
Map data
Sample
  • Complex: ABCB1
    • Protein or peptide: ATP-dependent translocase ABCB1
  • Ligand: (4~{S},11~{S},18~{S})-4,11-dimethyl-18-(sulfanylmethyl)-6,13,20-trithia-3,10,17,22,23,24-hexazatetracyclo[17.2.1.1^{5,8}.1^{12,15}]tetracosa-1(21),5(24),7,12(23),14,19(22)-hexaene-2,9,16-trione
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE
  • Ligand: MAGNESIUM ION
  • Ligand: Lauryl Maltose Neopentyl Glycol
  • Ligand: CHOLESTEROL HEMISUCCINATE
  • Ligand: water
KeywordsABC transporter / MEMBRANE PROTEIN
Function / homology
Function and homology information


Atorvastatin ADME / aldosterone secretion / Prednisone ADME / neural tissue regeneration / cellular response to nonylphenol / cellular response to borneol / response to codeine / cellular response to mycotoxin / daunorubicin transport / positive regulation of response to drug ...Atorvastatin ADME / aldosterone secretion / Prednisone ADME / neural tissue regeneration / cellular response to nonylphenol / cellular response to borneol / response to codeine / cellular response to mycotoxin / daunorubicin transport / positive regulation of response to drug / terpenoid transport / ceramide floppase activity / regulation of intestinal absorption / cellular response to external biotic stimulus / response to cyclosporin A / response to antineoplastic agent / positive regulation of establishment of Sertoli cell barrier / negative regulation of sensory perception of pain / carboxylic acid transmembrane transport / floppase activity / ceramide translocation / ABC-family proteins mediated transport / response to quercetin / carboxylic acid transmembrane transporter activity / establishment of blood-retinal barrier / protein localization to bicellular tight junction / phosphatidylethanolamine flippase activity / phosphatidylcholine floppase activity / response to thyroxine / xenobiotic transport across blood-brain barrier / establishment of blood-brain barrier / intercellular canaliculus / export across plasma membrane / P-type phospholipid transporter / cardiac muscle cell differentiation / xenobiotic detoxification by transmembrane export across the plasma membrane / transepithelial transport / cellular response to L-glutamate / ABC-type xenobiotic transporter / adult heart development / response to vitamin A / response to vitamin D / response to glucagon / intestinal absorption / response to glycoside / response to alcohol / ABC-type xenobiotic transporter activity / phospholipid translocation / cellular hyperosmotic salinity response / cellular response to alkaloid / female gonad development / maintenance of blood-brain barrier / cellular response to antibiotic / exploration behavior / ATPase-coupled transmembrane transporter activity / efflux transmembrane transporter activity / xenobiotic transmembrane transporter activity / cellular response to dexamethasone stimulus / response to cadmium ion / transmembrane transporter activity / xenobiotic transport / lactation / response to progesterone / proteasomal protein catabolic process / neurogenesis / regulation of chloride transport / placenta development / stem cell proliferation / cellular response to estradiol stimulus / brush border membrane / female pregnancy / circadian rhythm / G2/M transition of mitotic cell cycle / response to toxic substance / cellular response to tumor necrosis factor / epidermal growth factor receptor signaling pathway / heart development / cellular response to lipopolysaccharide / gene expression / response to hypoxia / apical plasma membrane / response to xenobiotic stimulus / ubiquitin protein ligase binding / cell surface / ATP hydrolysis activity / 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 speciesMus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsParey K / Januliene D / Gewering T / Urbatsch I / Zhang Q / Moeller A / Hilbi H / Schaefer LV / Kuprov I / Bordignon E / Seeger MA
Funding support Germany, 2 items
OrganizationGrant numberCountry
German Research Foundation (DFG)CRC944 Germany
German Research Foundation (DFG)INST 190-196-1 FUGG Germany
CitationJournal: Elife / Year: 2024
Title: Tracing the substrate translocation mechanism in P-glycoprotein.
Authors: Theresa Gewering / Deepali Waghray / Kristian Parey / Hendrik Jung / Nghi N B Tran / Joel Zapata / Pengyi Zhao / Hao Chen / Dovile Januliene / Gerhard Hummer / Ina Urbatsch / Arne Moeller / Qinghai Zhang /
Abstract: P-glycoprotein (Pgp) is a prototypical ATP-binding cassette (ABC) transporter of great biological and clinical significance.Pgp confers cancer multidrug resistance and mediates the bioavailability ...P-glycoprotein (Pgp) is a prototypical ATP-binding cassette (ABC) transporter of great biological and clinical significance.Pgp confers cancer multidrug resistance and mediates the bioavailability and pharmacokinetics of many drugs (Juliano and Ling, 1976; Ueda et al., 1986; Sharom, 2011). Decades of structural and biochemical studies have provided insights into how Pgp binds diverse compounds (Loo and Clarke, 2000; Loo et al., 2009; Aller et al., 2009; Alam et al., 2019; Nosol et al., 2020; Chufan et al., 2015), but how they are translocated through the membrane has remained elusive. Here, we covalently attached a cyclic substrate to discrete sites of Pgp and determined multiple complex structures in inward- and outward-facing states by cryoEM. In conjunction with molecular dynamics simulations, our structures trace the substrate passage across the membrane and identify conformational changes in transmembrane helix 1 (TM1) as regulators of substrate transport. In mid-transport conformations, TM1 breaks at glycine 72. Mutation of this residue significantly impairs drug transport of Pgp in vivo, corroborating the importance of its regulatory role. Importantly, our data suggest that the cyclic substrate can exit Pgp without the requirement of a wide-open outward-facing conformation, diverting from the common efflux model for Pgp and other ABC exporters. The substrate transport mechanism of Pgp revealed here pinpoints critical targets for future drug discovery studies of this medically relevant system.
History
DepositionApr 12, 2022-
Header (metadata) releaseApr 26, 2023-
Map releaseApr 26, 2023-
UpdateNov 6, 2024-
Current statusNov 6, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_14760.png

Downloads & links

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Map

FileDownload / File: emd_14760.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.57 Å/pix.
x 400 pix.
= 229.2 Å		0.57 Å/pix.
x 400 pix.
= 229.2 Å		0.57 Å/pix.
x 400 pix.
= 229.2 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.573 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.09
Minimum - Maximum-0.42848015 - 0.7401639
Average (Standard dev.)0.0013614252 (±0.018206846)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 229.20001 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_14760_msk_1.map
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Additional map: #1

Fileemd_14760_additional_1.map
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Additional map: #2

Fileemd_14760_additional_2.map
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Half map: #2

Fileemd_14760_half_map_1.map
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Half map: #1

Fileemd_14760_half_map_2.map
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Sample components

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Entire : ABCB1

EntireName: ABCB1
Components
  • Complex: ABCB1
    • Protein or peptide: ATP-dependent translocase ABCB1
  • Ligand: (4~{S},11~{S},18~{S})-4,11-dimethyl-18-(sulfanylmethyl)-6,13,20-trithia-3,10,17,22,23,24-hexazatetracyclo[17.2.1.1^{5,8}.1^{12,15}]tetracosa-1(21),5(24),7,12(23),14,19(22)-hexaene-2,9,16-trione
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE
  • Ligand: MAGNESIUM ION
  • Ligand: Lauryl Maltose Neopentyl Glycol
  • Ligand: CHOLESTEROL HEMISUCCINATE
  • Ligand: water

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Supramolecule #1: ABCB1

SupramoleculeName: ABCB1 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 140 kDa/nm

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Macromolecule #1: ATP-dependent translocase ABCB1

MacromoleculeName: ATP-dependent translocase ABCB1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: ABC-type xenobiotic transporter
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 146.077891 KDa
Recombinant expressionOrganism: Komagataella pastoris (fungus)
SequenceString: MELEEDLKGR ADKNFSKMGK KSKKEKKEKK PAVSVLTMFR YAGWLDRLYM LVGTLAAIIH GVALPLMMLI FGDMTDSFAS VGQVSKQST QMSEADKRAM FAKLEEEMTT YAYYYTGIGA GVLIVAYIQV SFWALAAGRQ IHKIRQKFFH AIMNQEIGWF D VHDVGELN ...String:
MELEEDLKGR ADKNFSKMGK KSKKEKKEKK PAVSVLTMFR YAGWLDRLYM LVGTLAAIIH GVALPLMMLI FGDMTDSFAS VGQVSKQST QMSEADKRAM FAKLEEEMTT YAYYYTGIGA GVLIVAYIQV SFWALAAGRQ IHKIRQKFFH AIMNQEIGWF D VHDVGELN TRLTDDVSKI NEGIGDKIGM FFQAMATFFG GFIIGFTRGW KLTLVILAIS PVLGLSAGIW AKILSSFTDK EL HAYAKAG AVAEEVLAAI RTVIAFGGQK KELERYNNNL EEAKRLGIKK AITANISMGA AFLLIYASYA LAFWYGTSLV ISK EYSIGQ VLTVFFSVLI GAFSVGQASP NIEAFANARG AAYEVFKIID NKPSIDSFSK SGHKPDNIQG NLEFKNIHFS YPSR KEVQI LKGLNLKVKS GQTVALVGNS GGGKSTTVQL MQRLYDPLDG MVSIDGQDIR TINVRYLREI IGVVSQEPVL FATTI AENI RYGREDVTMD EIEKAVKEAN AYDFIMKLPH QFDTLVGERG AQLSGGQKQR IAIARALVRN PKILLLDEAT SALDTE SEA VVQAALDKAR EGRTTIVIAH RLSTVRNADV IAGFDGGVIV EQGNHDELMR EKGIYFKLVM TQTAGNEIEL GNEAGKS KD EIDNLDMSSK DSGSSLIRRR STRKSITGPH DQDRKLSTKE ALDEDVPPAS FWRILKLNST EWPYFVVGIF AAIINGGL Q PAFSVIFSKV VGVFTNGGPP ETQRQNSNLF SLLFLILGII SFITFFLQGF TFGKAGEILT KRLRYMVFKS MLRQDVSWF DDPKNTTGAL TTRLANDAAQ VKGATGSRLA VIFQNIANLG TGIIISLIYG WQLTLLLLAI VPIIAIAGVV EMKMLSGQAL KDKKELEGS GKIATEAIEN FRTVVSLTRE QKFETMYAQS LQIPYRNAMK KAHVFGITFS FTQAMMYFSY AAAFRFGAYL V TQQLMTFE NVLLVFSAIC FGAMAVGQVS SFAPDYAKAT VSASHIIRII EKTPEIDSYS TQGLKPNMLE GNVQFSGVVF NY PTRPSIP VLQGLSLEVK KGQTLALVGS SGGGKSTVVQ LLERFYDPMA GSVFLDGKEI KQLNVQWLRA QLGIVSQEPI LFD RSIAEN IAYGDNSRVV SYEEIVRAAK EANIHQFIDS LPDKYNTRVG DKGTQLSGGQ KQRIAIARAL VRQPHILLLD EATS ALDTE SEKVVQEALD KAREGRTVIV IAHRLSTIQN ADLIVVIQNG KVKEHGTHQQ LLAQKGIYFS MVSVQAGAKR SLEEN LYFQ GGGASGGSWS HPQFEKAAAG GGSGGGSWSH PQFEKGSGHH HHHH

UniProtKB: ATP-dependent translocase ABCB1

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Macromolecule #2: (4~{S},11~{S},18~{S})-4,11-dimethyl-18-(sulfanylmethyl)-6,13,20-t...

MacromoleculeName: (4~{S},11~{S},18~{S})-4,11-dimethyl-18-(sulfanylmethyl)-6,13,20-trithia-3,10,17,22,23,24-hexazatetracyclo[17.2.1.1^{5,8}.1^{12,15}]tetracosa-1(21),5(24),7,12(23),14,19(22)-hexaene-2,9,16-trione
type: ligand / ID: 2 / Number of copies: 1 / Formula: JIZ
Molecular weightTheoretical: 494.634 Da
Chemical component information

ChemComp-JIZ:
(4~{S},11~{S},18~{S})-4,11-dimethyl-18-(sulfanylmethyl)-6,13,20-trithia-3,10,17,22,23,24-hexazatetracyclo[17.2.1.1^{5,8}.1^{12,15}]tetracosa-1(21),5(24),7,12(23),14,19(22)-hexaene-2,9,16-trione

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Macromolecule #3: ADENOSINE-5'-TRIPHOSPHATE

MacromoleculeName: ADENOSINE-5'-TRIPHOSPHATE / type: ligand / ID: 3 / Number of copies: 2 / Formula: ATP
Molecular weightTheoretical: 507.181 Da
Chemical component information

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM

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Macromolecule #4: MAGNESIUM ION

MacromoleculeName: MAGNESIUM ION / type: ligand / ID: 4 / Number of copies: 2 / Formula: MG
Molecular weightTheoretical: 24.305 Da

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Macromolecule #5: Lauryl Maltose Neopentyl Glycol

MacromoleculeName: Lauryl Maltose Neopentyl Glycol / type: ligand / ID: 5 / Number of copies: 1 / Formula: LMN
Molecular weightTheoretical: 1.005188 KDa
Chemical component information

ChemComp-AV0:
Lauryl Maltose Neopentyl Glycol

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Macromolecule #6: CHOLESTEROL HEMISUCCINATE

MacromoleculeName: CHOLESTEROL HEMISUCCINATE / type: ligand / ID: 6 / Number of copies: 3 / Formula: Y01
Molecular weightTheoretical: 486.726 Da
Chemical component information

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

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Macromolecule #7: water

MacromoleculeName: water / type: ligand / ID: 7 / Number of copies: 4 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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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

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 75.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 271467
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final 3D classificationSoftware - Name: RELION (ver. 3.1)
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

6c0v


Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementSpace: REAL / Protocol: FLEXIBLE FIT
Output model

PDB-7zka:
ABCB1 V978C mutant (mABCB1) in the outward facing state bound to AAC

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