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- PDB-6fn4: Apo form of UIC2 Fab complex of human-mouse chimeric ABCB1 (ABCB1HM) -

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Basic information

Entry
Database: PDB / ID: 6fn4
TitleApo form of UIC2 Fab complex of human-mouse chimeric ABCB1 (ABCB1HM)
Components
  • Apo form of Human-mouse chimeric ABCB1 (ABCB1HM) in complex with Antigen binding fragment of UIC2.
  • UIC2 Antigen Binding Fragment Light chain
  • UIC2 Antigen binding fragment Heavy chain
KeywordsMEMBRANE PROTEIN / Membrane Transport Protein ABCB1 ABC Exporter Small molecule inhibitor Antibody complex
Function / homology
Function and homology information


carboxylic acid transmembrane transport / carboxylic acid transmembrane transporter activity / hormone transport / cellular response to nonylphenol / cellular response to borneol / response to codeine / response to cyclosporin A / cellular response to mycotoxin / daunorubicin transport / positive regulation of response to drug ...carboxylic acid transmembrane transport / carboxylic acid transmembrane transporter activity / hormone transport / cellular response to nonylphenol / cellular response to borneol / response to codeine / response to cyclosporin A / cellular response to mycotoxin / daunorubicin transport / positive regulation of response to drug / terpenoid transport / ceramide floppase activity / negative regulation of sensory perception of pain / positive regulation of establishment of Sertoli cell barrier / regulation of intestinal absorption / cellular response to external biotic stimulus / response to quercetin / response to antineoplastic agent / ceramide translocation / floppase activity / Abacavir transmembrane transport / establishment of blood-retinal barrier / phosphatidylethanolamine flippase activity / protein localization to bicellular tight junction / external side of apical plasma membrane / phosphatidylcholine floppase activity / Atorvastatin ADME / response to thyroxine / xenobiotic transport across blood-brain barrier / establishment of blood-brain barrier / transepithelial transport / xenobiotic detoxification by transmembrane export across the plasma membrane / export across plasma membrane / P-type phospholipid transporter / ABC-type xenobiotic transporter / cellular response to L-glutamate / response to vitamin A / response to vitamin D / response to glycoside / ABC-type xenobiotic transporter activity / response to glucagon / intestinal absorption / response to alcohol / phospholipid translocation / Prednisone ADME / 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 / cellular response to dexamethasone stimulus / response to cadmium ion / transport across blood-brain barrier / lactation / xenobiotic metabolic process / regulation of chloride transport / response to progesterone / placenta development / stem cell proliferation / ABC-family proteins mediated transport / cellular response to estradiol stimulus / brush border membrane / female pregnancy / circadian rhythm / transmembrane transport / G2/M transition of mitotic cell cycle / cellular response to tumor necrosis factor / cellular response to lipopolysaccharide / response to hypoxia / apical plasma membrane / response to xenobiotic stimulus / ubiquitin protein ligase binding / cell surface / ATP hydrolysis activity / extracellular exosome / 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
1,2-Distearoyl-sn-glycerophosphoethanolamine / ATP-dependent translocase ABCB1
Similarity search - Component
Biological speciesHomo sapiens (human)
Mus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.14 Å
AuthorsAlam, A. / Locher, K.P.
Funding support Switzerland, United States, 3items
OrganizationGrant numberCountry
Swiss National Science Foundation Switzerland
European Molecular Biology Organization Switzerland
National Institutes of Health United States
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.
History
DepositionFeb 2, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 21, 2018Provider: repository / Type: Initial release
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Revision 1.1Feb 28, 2018Group: Author supporting evidence / Database references / Category: citation / pdbx_audit_support
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Revision 1.2Mar 7, 2018Group: Database references / Category: citation
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Revision 1.3Dec 11, 2019Group: Other / Category: atom_sites
Item: _atom_sites.fract_transf_matrix[1][1] / _atom_sites.fract_transf_matrix[2][2] / _atom_sites.fract_transf_matrix[3][3]
Revision 1.4Jul 29, 2020Group: Data collection / Derived calculations / Structure summary
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Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 1.5Jun 2, 2021Group: Structure summary / Category: chem_comp / Item: _chem_comp.pdbx_synonyms
Revision 1.6Oct 16, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
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Revision 1.7Jul 9, 2025Group: Data collection / Category: em_admin / em_software / Item: _em_admin.last_update / _em_software.name
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Structure visualization

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Structure viewerMolecule:
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Assembly

Deposited unit
A: Apo form of Human-mouse chimeric ABCB1 (ABCB1HM) in complex with Antigen binding fragment of UIC2.
B: UIC2 Antigen Binding Fragment Light chain
C: UIC2 Antigen binding fragment Heavy chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)191,3977
Polymers189,9853
Non-polymers1,4124
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area7940 Å2
ΔGint-37 kcal/mol
Surface area75380 Å2
MethodPISA

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Components

#1: Protein Apo form of Human-mouse chimeric ABCB1 (ABCB1HM) in complex with Antigen binding fragment of UIC2.


Mass: 141283.156 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human) / References: UniProt: P08183*PLUS
#2: Antibody UIC2 Antigen Binding Fragment Light chain


Mass: 24321.039 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Mus musculus (house mouse)
#3: Antibody UIC2 Antigen binding fragment Heavy chain


Mass: 24381.281 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Mus musculus (house mouse)
#4: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
#5: Chemical ChemComp-3PE / 1,2-Distearoyl-sn-glycerophosphoethanolamine / 3-SN-PHOSPHATIDYLETHANOLAMINE / 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOETHANOLAMINE


Mass: 748.065 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C41H82NO8P / Comment: phospholipid*YM
Has protein modificationY
Sequence detailsUniprot IDs: Human ABCB1 P08183. Mouse ABCB1 P21447

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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
1Apo Human-mouse chimeric ABCB1 (ABCB1HM) complex with UIC2 fabCOMPLEX#1-#30MULTIPLE SOURCES
2Apo Human-mouse chimeric ABCB1 (ABCB1HM) complex with UIC2 fabCOMPLEX#11RECOMBINANT
3Apo Human-mouse chimeric ABCB1 (ABCB1HM) complex with UIC2 fabCOMPLEX#2-#31RECOMBINANT
Molecular weight
IDEntity assembly-IDValue (°)Experimental value
110.195 MDaNO
220.142 MDaNO
330.0487 MDaNO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Homo sapiens (human)9606
23Mus musculus (house mouse)10090
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
12Homo sapiens (human)9606
23Mus musculus (house mouse)10090
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: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD
Image recordingElectron dose: 0.9 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
EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 4.14 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 517053 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.01212971
ELECTRON MICROSCOPYf_angle_d0.72217559
ELECTRON MICROSCOPYf_dihedral_angle_d6.8437672
ELECTRON MICROSCOPYf_chiral_restr0.0462007
ELECTRON MICROSCOPYf_plane_restr0.0052218

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