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- PDB-6fn1: Zosuquidar and UIC2 Fab complex of human-mouse chimeric ABCB1 (AB... -

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Basic information

Entry
Database: PDB / ID: 6fn1
TitleZosuquidar and UIC2 Fab complex of human-mouse chimeric ABCB1 (ABCB1HM)
Components
  • Human-mouse chimeric ABCB1 (ABCBHM)
  • UIC2 Antigen Binding Fragment Heavy Chain
  • UIC2 Antigen Binding Fragment Light chain
KeywordsMEMBRANE PROTEIN / Membrane Transport Protein ABCB1 ABC Exporter Small molecule inhibitor Antibody complex
Function / homologyType I protein exporter / ABC transporter-like / ABC-family proteins mediated transport / Abacavir transmembrane transport / ABC transporter integral membrane type-1 fused domain profile. / ATP-binding cassette, ABC transporter-type domain profile. / ABC transporters family signature. / ABC transporter transmembrane region / ABC transporter / ABC transporter type 1, transmembrane domain superfamily ...Type I protein exporter / ABC transporter-like / ABC-family proteins mediated transport / Abacavir transmembrane transport / ABC transporter integral membrane type-1 fused domain profile. / ATP-binding cassette, ABC transporter-type domain profile. / ABC transporters family signature. / ABC transporter transmembrane region / ABC transporter / ABC transporter type 1, transmembrane domain superfamily / Multidrug resistance protein 1 / P-loop containing nucleoside triphosphate hydrolase / ABC transporter, conserved site / ABC transporter type 1, transmembrane domain / AAA+ ATPase domain / ceramide translocation / ceramide-translocating ATPase activity / positive regulation of anion channel activity / phosphatidylethanolamine-translocating ATPase activity / ec:7.6.2.2: / phosphatidylcholine-translocating ATPase activity / regulation of response to osmotic stress / phospholipid translocation / xenobiotic transmembrane transporting ATPase activity / stem cell proliferation / ATPase activity, coupled to transmembrane movement of substances / transporter activity / regulation of chloride transport / transmembrane transport / apical plasma membrane / G2/M transition of mitotic cell cycle / response to drug / cell surface / extracellular exosome / membrane / integral component of membrane / ATP binding / plasma membrane / Multidrug resistance protein 1
Function and homology information
Specimen sourceHomo sapiens (human)
Mus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / 3.58 Å resolution
AuthorsAlam, A. / Locher, K.P.
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.
Validation Report
SummaryFull reportAbout validation report
DateDeposition: Feb 2, 2018 / Release: Feb 21, 2018
RevisionDateData content typeGroupCategoryItemProviderType
1.0Feb 21, 2018Structure modelrepositoryInitial release
1.1Feb 28, 2018Structure modelAdvisory / Author supporting evidence / Database references / Derived calculationscitation / pdbx_audit_support / pdbx_unobs_or_zero_occ_atoms / struct_conn_citation.journal_abbrev / _citation.pdbx_database_id_PubMed / _citation.title / _pdbx_audit_support.funding_organization
1.2Mar 7, 2018Structure modelDatabase referencescitation_citation.journal_volume / _citation.page_first / _citation.page_last

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Structure visualization

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Assembly

Deposited unit
A: Human-mouse chimeric ABCB1 (ABCBHM)
B: UIC2 Antigen Binding Fragment Light chain
C: UIC2 Antigen Binding Fragment Heavy Chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)188,1418
Polyers186,4223
Non-polymers1,7195
Water0
1


TypeNameSymmetry operationNumber
identity operation1_5551
Buried area (Å2)6960
ΔGint (kcal/M)-32
Surface area (Å2)69250
MethodPISA

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Components

#1: Protein/peptide Human-mouse chimeric ABCB1 (ABCBHM)


Mass: 137719.953 Da / Num. of mol.: 1 / Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): HEK / Production host: Homo sapiens (human) / References: UniProt: P08183*PLUS
#2: Protein/peptide UIC2 Antigen Binding Fragment Light chain


Mass: 24321.039 Da / Num. of mol.: 1 / Source: (gene. exp.) Mus musculus (house mouse) / Cell line (production host): Hybridoma / Production host: Mus musculus (house mouse)
#3: Protein/peptide UIC2 Antigen Binding Fragment Heavy Chain


Mass: 24381.281 Da / Num. of mol.: 1 / Source: (gene. exp.) Mus musculus (house mouse) / Cell line (production host): Hybridoma / Production host: Mus musculus (house mouse)
#4: Chemical ChemComp-NAG / N-ACETYL-D-GLUCOSAMINE


Mass: 221.208 Da / Num. of mol.: 3 / Formula: C8H15NO6 / N-Acetylglucosamine
#5: Chemical ChemComp-ZQU / Zosuquidar


Mass: 527.604 Da / Num. of mol.: 2 / Formula: C32H31F2N3O2 / Zosuquidar

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Experimental details

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Experiment

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

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Sample preparation

Component
IDNameTypeEntity IDParent IDSource
1Human-mouse chimeric ABCB1 (ABCB1HM) complex with UIC2 fab and zosuquidarCOMPLEX1,2,30MULTIPLE SOURCES
2Human-mouse chimeric ABCB1 (ABCB1HM) complex with UIC2 fab and zosuquidarCOMPLEX11RECOMBINANT
3Human-mouse chimeric ABCB1 (ABCB1HM) complex with UIC2 fab and zosuquidarCOMPLEX2,31RECOMBINANT
Molecular weightValue: 0.195 MDa / Experimental value: NO
Source (natural)
IDEntity assembly IDNcbi tax IDOrganism
129606Homo sapiens (human)
2310090Mus musculus (house mouse)
Source (recombinant)
IDEntity assembly IDNcbi tax IDOrganism
129606Homo sapiens (human)
2310090Mus musculus (house mouse)
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
MicroscopyMicroscope model: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy
Image recordingElectron dose: 1.54 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.12_2829: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1
3D reconstructionResolution: 3.58 Å / Resolution method: FSC 0.143 CUT-OFF / Number of particles: 231969 / Symmetry type: POINT
Refine LS restraints
Refine IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.01013025
ELECTRON MICROSCOPYf_angle_d1.19217661
ELECTRON MICROSCOPYf_dihedral_angle_d7.7358441
ELECTRON MICROSCOPYf_chiral_restr0.0662016
ELECTRON MICROSCOPYf_plane_restr0.0082225

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