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- PDB-8y6h: P-glycoprotein in complex with UIC2 Fab and triple elacridar mole... -

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Basic information

Entry
Database: PDB / ID: 8y6h
TitleP-glycoprotein in complex with UIC2 Fab and triple elacridar molecules in LMNG detergent
Components
  • ATP-dependent translocase ABCB1,mNeonGreen
  • UIC2 Fab heavy chain
  • UIC2 Fab light chain
KeywordsMEMBRANE PROTEIN / ABC transporter / elacridar / P-glycoprotein
Function / homology
Function and homology information


positive regulation of anion channel activity / ceramide translocation / terpenoid transport / ceramide floppase activity / carboxylic acid transmembrane transport / carboxylic acid transmembrane transporter activity / floppase activity / Abacavir transmembrane transport / external side of apical plasma membrane / regulation of response to osmotic stress ...positive regulation of anion channel activity / ceramide translocation / terpenoid transport / ceramide floppase activity / carboxylic acid transmembrane transport / carboxylic acid transmembrane transporter activity / floppase activity / Abacavir transmembrane transport / external side of apical plasma membrane / regulation of response to osmotic stress / Atorvastatin ADME / phosphatidylcholine floppase activity / phosphatidylethanolamine flippase activity / xenobiotic transport across blood-brain barrier / xenobiotic detoxification by transmembrane export across the plasma membrane / export across plasma membrane / ABC-type xenobiotic transporter / transepithelial transport / P-type phospholipid transporter / ABC-type xenobiotic transporter activity / phospholipid translocation / Prednisone ADME / xenobiotic transmembrane transporter activity / efflux transmembrane transporter activity / transmembrane transporter activity / transport across blood-brain barrier / ATPase-coupled transmembrane transporter activity / xenobiotic metabolic process / bioluminescence / regulation of chloride transport / stem cell proliferation / ABC-family proteins mediated transport / transmembrane transport / G2/M transition of mitotic cell cycle / response to xenobiotic stimulus / apical plasma membrane / 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 / Green fluorescent protein-related / Green fluorescent protein / Green fluorescent protein / 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 / Green fluorescent protein-related / Green fluorescent protein / Green fluorescent protein / 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
elacridar / mNeonGreen / ATP-dependent translocase ABCB1
Similarity search - Component
Biological speciesHomo sapiens (human)
Mus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.49 Å
AuthorsHamaguchi-Suzuki, N. / Adachi, N. / Moriya, T. / Kawasaki, M. / Suzuki, K. / Anzai, N. / Senda, T. / Murata, T.
Funding support Japan, 3items
OrganizationGrant numberCountry
Japan Agency for Medical Research and Development (AMED)JP21am0101083 Japan
Japan Agency for Medical Research and Development (AMED)JP23ama121013 Japan
Japan Society for the Promotion of Science (JSPS)18H05425 Japan
CitationJournal: Biochem Biophys Res Commun / Year: 2024
Title: Cryo-EM structure of P-glycoprotein bound to triple elacridar inhibitor molecules.
Authors: Norie Hamaguchi-Suzuki / Naruhiko Adachi / Toshio Moriya / Satoshi Yasuda / Masato Kawasaki / Kano Suzuki / Satoshi Ogasawara / Naohiko Anzai / Toshiya Senda / Takeshi Murata /
Abstract: P-glycoprotein (P-gp) is an ATP-binding cassette transporter known for its roles in expelling xenobiotic compounds from cells and contributing to cellular drug resistance through multidrug efflux. ...P-glycoprotein (P-gp) is an ATP-binding cassette transporter known for its roles in expelling xenobiotic compounds from cells and contributing to cellular drug resistance through multidrug efflux. This mechanism is particularly problematic in cancer cells, where it diminishes the therapeutic efficacy of anticancer drugs. P-gp inhibitors, such as elacridar, have been developed to circumvent the decrease in drug efficacy due to P-gp efflux. An earlier study reported the cryo-EM structure of human P-gp-Fab (MRK-16) complex bound by two elacridar molecules, at a resolution of 3.6 Å. In this study, we have obtained a higher resolution (2.5 Å) structure of the P-gp- Fab (UIC2) complex bound by three elacridar molecules. This finding, which exposes a larger space for compound-binding sites than previously acknowledged, has significant implications for the development of more selective inhibitors and enhances our understanding of the compound recognition mechanism of P-gp.
History
DepositionFeb 2, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Apr 17, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: ATP-dependent translocase ABCB1,mNeonGreen
B: UIC2 Fab light chain
C: UIC2 Fab heavy chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)220,9296
Polymers219,2383
Non-polymers1,6913
Water0
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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


Mass: 170535.812 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ABCB1, MDR1, PGY1, blFP-Y3 / Production host: Homo sapiens (human)
References: UniProt: P08183, UniProt: A0A1S4NYF2, ABC-type xenobiotic transporter, P-type phospholipid transporter
#2: Antibody UIC2 Fab 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 Fab 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: 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.: 3 / Source method: obtained synthetically / Formula: C34H33N3O5 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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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: Multidrug resistance proteinATP-binding cassette transporter
Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 291 K

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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 FIELDBright-field microscopy / Nominal defocus max: 20000 nm / Nominal defocus min: 800 nm / Cs: 2.7 mm
Image recordingElectron dose: 48.8 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 4482

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Processing

EM software
IDNameVersionCategory
7Coot0.9.8.92model fitting
9PHENIX1.20.1model refinement
10RELION3.1initial Euler assignment
11RELION3.1final Euler assignment
13cryoSPARC4.2.13D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.49 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 142821 / Symmetry type: POINT
Atomic model buildingSpace: RECIPROCAL
Atomic model buildingPDB-ID: 6QEX

6qex


Accession code: 6QEX / Source name: PDB / Type: experimental model
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 110.82 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.01187546
ELECTRON MICROSCOPYf_angle_d0.722810264
ELECTRON MICROSCOPYf_chiral_restr0.04891189
ELECTRON MICROSCOPYf_plane_restr0.00561259
ELECTRON MICROSCOPYf_dihedral_angle_d6.35251065

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