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

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Basic information

Entry
Database: PDB / ID: 7zka
TitleABCB1 V978C mutant (mABCB1) in the outward facing state bound to AAC
ComponentsATP-dependent translocase ABCB1
KeywordsMEMBRANE PROTEIN / ABC transporter
Function / homology
Function and homology information


hormone transport / 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 / regulation of intestinal absorption ...hormone transport / 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 / regulation of intestinal absorption / response to quercetin / cellular response to external biotic stimulus / response to antineoplastic agent / positive regulation of establishment of Sertoli cell barrier / Prednisone ADME / terpenoid transport / ceramide floppase activity / response to glycoside / floppase activity / ceramide translocation / establishment of blood-retinal barrier / protein localization to bicellular tight junction / response to alcohol / ABC-family proteins mediated transport / response to thyroxine / establishment of blood-brain barrier / phosphatidylethanolamine flippase activity / xenobiotic transport across blood-brain barrier / phosphatidylcholine floppase activity / xenobiotic detoxification by transmembrane export across the plasma membrane / cellular response to L-glutamate / intercellular canaliculus / export across plasma membrane / ABC-type xenobiotic transporter / response to vitamin D / P-type phospholipid transporter / response to vitamin A / ABC-type xenobiotic transporter activity / 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 / cellular response to estradiol stimulus / response to progesterone / female pregnancy / 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
ADENOSINE-5'-TRIPHOSPHATE / Chem-JIZ / CHOLESTEROL HEMISUCCINATE / ATP-dependent translocase ABCB1
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsParey, K. / Januliene, D. / Gewering, T. / Urbatsch, I. / Zhang, Q. / Moeller, A.
Funding support Germany, 2items
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, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 26, 2023Provider: repository / Type: Initial release
Revision 1.1Mar 20, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / citation_author / em_3d_fitting_list
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_3d_fitting_list.accession_code / _em_3d_fitting_list.initial_refinement_model_id / _em_3d_fitting_list.source_name / _em_3d_fitting_list.type
Revision 1.2Nov 6, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: ATP-dependent translocase ABCB1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)150,10110
Polymers146,0781
Non-polymers4,0239
Water724
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area2150 Å2
ΔGint-26 kcal/mol
Surface area46700 Å2
MethodPISA

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Components

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Protein , 1 types, 1 molecules A

#1: Protein ATP-dependent translocase ABCB1 / ATP-binding cassette sub-family B member 1A / MDR1A / Multidrug resistance protein 1A / Multidrug ...ATP-binding cassette sub-family B member 1A / MDR1A / Multidrug resistance protein 1A / Multidrug resistance protein 3 / P-glycoprotein 3 / Phospholipid transporter ABCB1


Mass: 146077.891 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Abcb1a, Abcb4, Mdr1a, Mdr3, Pgy-3, Pgy3 / Production host: Komagataella pastoris (fungus)
References: UniProt: P21447, ABC-type xenobiotic transporter, P-type phospholipid transporter

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Non-polymers , 6 types, 13 molecules

#2: Chemical 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


Mass: 494.634 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H18N6O3S4 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-ATP / ADENOSINE-5'-TRIPHOSPHATE


Mass: 507.181 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H16N5O13P3 / Comment: ATP, energy-carrying molecule*YM
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#5: Chemical ChemComp-LMN / Lauryl Maltose Neopentyl Glycol / 2,2-didecylpropane-1,3-bis-b-D-maltopyranoside


Mass: 1005.188 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C47H88O22 / Comment: detergent*YM
#6: Chemical ChemComp-Y01 / CHOLESTEROL HEMISUCCINATE


Mass: 486.726 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C31H50O4
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 4 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: ABCB1 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 140 kDa/nm / Experimental value: NO
Source (natural)Organism: Mus musculus (house mouse)
Source (recombinant)Organism: Komagataella pastoris (fungus)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 75 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.19.2_4158: / Classification: refinement
EM software
IDNameVersionCategory
7Coot0.9.3model fitting
9PHENIX1.19.2model refinement
12RELION3.1classification
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 271467 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL
Atomic model buildingPDB-ID: 6C0V

6c0v


Accession code: 6C0V / Source name: PDB / Type: experimental model
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0029618
ELECTRON MICROSCOPYf_angle_d0.55413037
ELECTRON MICROSCOPYf_dihedral_angle_d7.4941364
ELECTRON MICROSCOPYf_chiral_restr0.0421506
ELECTRON MICROSCOPYf_plane_restr0.0051620

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