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- PDB-7a6c: Nanodisc reconstituted human ABCB1 in complex with MRK16 Fab and ... -

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Basic information

Entry
Database: PDB / ID: 7a6c
TitleNanodisc reconstituted human ABCB1 in complex with MRK16 Fab and elacridar
Components
  • If kappa light chain
  • MRK16 Fab-fragment heavy chain
  • Multidrug resistance protein 1
KeywordsTRANSPORT PROTEIN / P-glycoprotein / MDR1 / nanodisc
Function / homology
Function and homology information


terpenoid transport / ceramide floppase activity / phosphatidylethanolamine floppase activity / carboxylic acid transmembrane transport / regulation of chloride transport / floppase activity / ceramide translocation / Abacavir transmembrane transport / carboxylic acid transmembrane transporter activity / phosphatidylethanolamine flippase activity ...terpenoid transport / ceramide floppase activity / phosphatidylethanolamine floppase activity / carboxylic acid transmembrane transport / regulation of chloride transport / floppase activity / ceramide translocation / Abacavir transmembrane transport / carboxylic acid transmembrane transporter activity / phosphatidylethanolamine flippase activity / phosphatidylcholine floppase activity / xenobiotic transport across blood-brain barrier / stem cell proliferation / external side of apical plasma membrane / Atorvastatin ADME / export across plasma membrane / P-type phospholipid transporter / transepithelial transport / xenobiotic detoxification by transmembrane export across the plasma membrane / ABC-type xenobiotic transporter / phospholipid translocation / Prednisone ADME / ABC-type xenobiotic transporter activity / xenobiotic transmembrane transporter activity / efflux transmembrane transporter activity / ATPase-coupled transmembrane transporter activity / immunoglobulin complex / transport across blood-brain barrier / transmembrane transporter activity / xenobiotic metabolic process / G2/M transition of mitotic cell cycle / ABC-family protein mediated transport / transmembrane transport / adaptive immune response / apical plasma membrane / response to xenobiotic stimulus / ubiquitin protein ligase binding / cell surface / ATP hydrolysis activity / extracellular exosome / extracellular region / 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 / Immunoglobulin V-Type / Immunoglobulin V-set domain / ABC transporter-like, conserved site / ABC transporters family signature. ...: / 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 / Immunoglobulin V-Type / Immunoglobulin V-set domain / ABC transporter-like, conserved site / ABC transporters family signature. / Immunoglobulin V-set domain / ABC transporter / ABC transporter-like, ATP-binding domain / ATP-binding cassette, ABC transporter-type domain profile. / Immunoglobulin/major histocompatibility complex, conserved site / Immunoglobulins and major histocompatibility complex proteins signature. / Immunoglobulin subtype / Immunoglobulin / Immunoglobulin C-Type / Immunoglobulin C1-set / Immunoglobulin C1-set domain / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / ATPases associated with a variety of cellular activities / AAA+ ATPase domain / Immunoglobulin-like fold / Immunoglobulins / Immunoglobulin-like / Sandwich / P-loop containing nucleoside triphosphate hydrolase / Mainly Beta
Similarity search - Domain/homology
CHOLESTEROL / elacridar / If kappa light chain / ATP-dependent translocase ABCB1
Similarity search - Component
Biological speciesHomo sapiens (human)
Mus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.6 Å
AuthorsNosol, K. / Locher, K.P.
Funding support Switzerland, 1items
OrganizationGrant numberCountry
Swiss National Science Foundation310030_189111 Switzerland
CitationJournal: Proc Natl Acad Sci U S A / Year: 2020
Title: Cryo-EM structures reveal distinct mechanisms of inhibition of the human multidrug transporter ABCB1.
Authors: Kamil Nosol / Ksenija Romane / Rossitza N Irobalieva / Amer Alam / Julia Kowal / Naoya Fujita / Kaspar P Locher /
Abstract: ABCB1 detoxifies cells by exporting diverse xenobiotic compounds, thereby limiting drug disposition and contributing to multidrug resistance in cancer cells. Multiple small-molecule inhibitors and ...ABCB1 detoxifies cells by exporting diverse xenobiotic compounds, thereby limiting drug disposition and contributing to multidrug resistance in cancer cells. Multiple small-molecule inhibitors and inhibitory antibodies have been developed for therapeutic applications, but the structural basis of their activity is insufficiently understood. We determined cryo-EM structures of nanodisc-reconstituted, human ABCB1 in complex with the Fab fragment of the inhibitory, monoclonal antibody MRK16 and bound to a substrate (the antitumor drug vincristine) or to the potent inhibitors elacridar, tariquidar, or zosuquidar. We found that inhibitors bound in pairs, with one molecule lodged in the central drug-binding pocket and a second extending into a phenylalanine-rich cavity that we termed the "access tunnel." This finding explains how inhibitors can act as substrates at low concentration, but interfere with the early steps of the peristaltic extrusion mechanism at higher concentration. Our structural data will also help the development of more potent and selective ABCB1 inhibitors.
History
DepositionAug 25, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 14, 2020Provider: repository / Type: Initial release
Revision 1.0Oct 14, 2020Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Oct 14, 2020Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Oct 14, 2020Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Oct 14, 2020Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.0Oct 14, 2020Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Oct 14, 2020Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Oct 14, 2020Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.0Oct 14, 2020Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Oct 14, 2020Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Oct 14, 2020Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Oct 28, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Nov 13, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _em_admin.last_update / _pdbx_entry_details.has_protein_modification
Revision 1.3Jul 2, 2025Group: Data collection / Category: em_admin / em_software / Item: _em_admin.last_update / _em_software.name
Revision 1.1Jul 2, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Data processing / Experimental summary / Data content type: EM metadata / EM metadata / Category: em_admin / em_software / Data content type: EM metadata / EM metadata / Item: _em_admin.last_update / _em_software.name

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Assembly

Deposited unit
A: Multidrug resistance protein 1
B: If kappa light chain
C: MRK16 Fab-fragment heavy chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)194,17815
Polymers189,1843
Non-polymers4,99412
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area10980 Å2
ΔGint-12 kcal/mol
Surface area70700 Å2
MethodPISA

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Components

#1: Protein Multidrug resistance protein 1 / ATP-binding cassette sub-family B member 1 / P-glycoprotein 1


Mass: 141628.781 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ABCB1, MDR1, PGY1 / Production host: Homo sapiens (human)
References: UniProt: P08183, ABC-type xenobiotic transporter, P-type phospholipid transporter
#2: Antibody If kappa light chain


Mass: 24139.758 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Igkc, Igk-C / Production host: Homo sapiens (human) / References: UniProt: A2NHM3
#3: Antibody MRK16 Fab-fragment heavy chain


Mass: 23415.236 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Homo sapiens (human)
#4: Chemical ChemComp-R0Z / elacridar / ~{N}-[4-[2-(6,7-dimethoxy-3,4-dihydro-1~{H}-isoquinolin-2-yl)ethyl]phenyl]-5-methoxy-9-oxidanylidene-10~{H}-acridine-4-carboxamide


Mass: 563.643 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C34H33N3O5 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical
ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 10 / Source method: obtained synthetically / Formula: C27H46O
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

Component
IDNameTypeEntity IDParent-IDSource
1Nanodisc reconstituted human ABCB1 in complex with MRK16 Fab and elacridarCOMPLEX#1-#30MULTIPLE SOURCES
2Multidrug resistance protein 1COMPLEX#11RECOMBINANT
3MRK16 Fab-fragment light and heavy chainCOMPLEX#2-#31RECOMBINANT
Molecular weightValue: 0.24 MDa / Experimental value: YES
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
22Homo sapiens (human)9606
33Mus musculus (house mouse)10090
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
22Homo sapiens (human)9606
33Homo sapiens (human)9606
Buffer solutionpH: 7.4
SpecimenConc.: 0.4 mg/ml / Embedding 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: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Cs: 2.7 mm / C2 aperture diameter: 100 µm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 32 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.15_3459: / Classification: refinement
EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 241885 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.01712998
ELECTRON MICROSCOPYf_angle_d1.29817654
ELECTRON MICROSCOPYf_dihedral_angle_d11.7247758
ELECTRON MICROSCOPYf_chiral_restr0.0662048
ELECTRON MICROSCOPYf_plane_restr0.0072169

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