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- EMDB-14761: ABCB1 V978C mutant (mABCB1) in the inward facing state -

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Entry
Database: EMDB / ID: EMD-14761
TitleABCB1 V978C mutant (mABCB1) in the inward facing state
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: (4S,11S,18S)-4-[[(2,4-dinitrophenyl)disulfanyl]methyl]-11,18-dimethyl-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
KeywordsABC transporter / MEMBRANE PROTEIN
Function / homology
Function and homology information


hormone transport / cellular response to nonylphenol / cellular response to borneol / response to codeine / response to cyclosporin A / Atorvastatin ADME / cellular response to mycotoxin / daunorubicin transport / positive regulation of response to drug / negative regulation of sensory perception of pain ...hormone transport / cellular response to nonylphenol / cellular response to borneol / response to codeine / response to cyclosporin A / Atorvastatin ADME / cellular response to mycotoxin / daunorubicin transport / positive regulation of response to drug / negative regulation of sensory perception of pain / positive regulation of establishment of Sertoli cell barrier / regulation of intestinal absorption / response to quercetin / cellular response to external biotic stimulus / response to antineoplastic agent / Prednisone ADME / response to glycoside / terpenoid transport / ceramide floppase activity / ceramide translocation / floppase activity / establishment of blood-retinal barrier / protein localization to bicellular tight junction / ABC-family proteins mediated transport / response to thyroxine / establishment of blood-brain barrier / phosphatidylethanolamine flippase activity / phosphatidylcholine floppase activity / xenobiotic detoxification by transmembrane export across the plasma membrane / xenobiotic transport across blood-brain barrier / intercellular canaliculus / cellular response to L-glutamate / response to vitamin D / export across plasma membrane / P-type phospholipid transporter / ABC-type xenobiotic transporter / response to vitamin A / ABC-type xenobiotic transporter activity / response to alcohol / intestinal absorption / response to glucagon / phospholipid translocation / cellular response to antibiotic / cellular hyperosmotic salinity response / maintenance of blood-brain barrier / cellular response to alkaloid / efflux transmembrane transporter activity / xenobiotic transmembrane transporter activity / transmembrane transporter activity / ATPase-coupled transmembrane transporter activity / response to cadmium ion / lactation / cellular response to dexamethasone stimulus / response to progesterone / female pregnancy / cellular response to estradiol stimulus / brush border membrane / placenta development / circadian rhythm / cellular response to tumor necrosis factor / cellular response to lipopolysaccharide / response to hypoxia / response to xenobiotic stimulus / apical plasma membrane / ATP hydrolysis activity / ATP binding / 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: 4.7 Å
AuthorsParey K / Januliene D / Gewering T / Moeller A / Vecchis D / Striednig B / 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-
UpdateOct 23, 2024-
Current statusOct 23, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_14761.png

Downloads & links

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Map

FileDownload / File: emd_14761.map.gz / Format: CCP4 / Size: 83.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.84 Å/pix.
x 280 pix.
= 234.36 Å		0.84 Å/pix.
x 280 pix.
= 234.36 Å		0.84 Å/pix.
x 280 pix.
= 234.36 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.837 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.12
Minimum - Maximum-0.6475247 - 0.80098623
Average (Standard dev.)0.0016596048 (±0.022524042)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions280280280
Spacing280280280
CellA=B=C: 234.36 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_14761_msk_1.map
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Additional map: unsharpened map

Fileemd_14761_additional_1.map
Annotationunsharpened map
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Half map: #2

Fileemd_14761_half_map_1.map
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Half map: #1

Fileemd_14761_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: (4S,11S,18S)-4-[[(2,4-dinitrophenyl)disulfanyl]methyl]-11,18-dimethyl-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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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: (4S,11S,18S)-4-[[(2,4-dinitrophenyl)disulfanyl]methyl]-11,18-dime...

MacromoleculeName: (4S,11S,18S)-4-[[(2,4-dinitrophenyl)disulfanyl]methyl]-11,18-dimethyl-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: 3 / Number of copies: 1 / Formula: JJI
Molecular weightTheoretical: 692.79 Da
Chemical component information

ChemComp-JJI:
(4S,11S,18S)-4-[[(2,4-dinitrophenyl)disulfanyl]methyl]-11,18-dimethyl-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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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: 4.7 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 343873
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-7zkb:
ABCB1 V978C mutant (mABCB1) in the inward facing state

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