[English] 日本語
Yorodumi
- PDB-8y6i: P-glycoprotein in complex with UIC2 Fab and triple elacridar mole... -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: PDB / ID: 8y6i
TitleP-glycoprotein in complex with UIC2 Fab and triple elacridar molecules in nanodisc
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


hormone transport / phosphatidylethanolamine floppase activity / cellular response to nonylphenol / cellular response to borneol / response to codeine / cellular response to mycotoxin / daunorubicin transport / positive regulation of response to drug / terpenoid transport / ceramide floppase activity ...hormone transport / phosphatidylethanolamine floppase activity / cellular response to nonylphenol / cellular response to borneol / response to codeine / cellular response to mycotoxin / daunorubicin transport / positive regulation of response to drug / terpenoid transport / ceramide floppase activity / regulation of intestinal absorption / cellular response to external biotic stimulus / response to cyclosporin A / response to antineoplastic agent / positive regulation of establishment of Sertoli cell barrier / negative regulation of sensory perception of pain / carboxylic acid transmembrane transport / floppase activity / ceramide translocation / Abacavir transmembrane transport / response to quercetin / carboxylic acid transmembrane transporter activity / establishment of blood-retinal barrier / protein localization to bicellular tight junction / phosphatidylethanolamine flippase activity / phosphatidylcholine floppase activity / external side of apical plasma membrane / Atorvastatin ADME / xenobiotic transport across blood-brain barrier / response to thyroxine / establishment of blood-brain barrier / export across plasma membrane / xenobiotic detoxification by transmembrane export across the plasma membrane / P-type phospholipid transporter / transepithelial transport / cellular response to L-glutamate / ABC-type xenobiotic transporter / response to vitamin A / response to vitamin D / response to glucagon / intestinal absorption / response to glycoside / response to alcohol / Prednisone ADME / ABC-type xenobiotic transporter activity / phospholipid translocation / cellular hyperosmotic salinity response / cellular response to alkaloid / maintenance of blood-brain barrier / cellular response to antibiotic / ATPase-coupled transmembrane transporter activity / efflux transmembrane transporter activity / xenobiotic transmembrane transporter activity / cellular response to dexamethasone stimulus / transmembrane transporter activity / response to cadmium ion / transport across blood-brain barrier / lactation / response to progesterone / xenobiotic metabolic process / regulation of chloride transport / placenta development / bioluminescence / stem cell proliferation / cellular response to estradiol stimulus / brush border membrane / female pregnancy / circadian rhythm / ABC-family proteins mediated transport / 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 / 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
1,2-Distearoyl-sn-glycerophosphoethanolamine / CHOLESTEROL / 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: 2.54 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
Revision 1.1Nov 13, 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
Revision 1.2Nov 27, 2024Group: Data collection / Category: em_admin / Item: _em_admin.last_update

-
Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
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)226,31719
Polymers219,2383
Non-polymers7,07916
Water00
1


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

-
Components

-
Protein , 1 types, 1 molecules A

#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

-
Antibody , 2 types, 2 molecules BC

#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)

-
Non-polymers , 3 types, 16 molecules

#4: Chemical
ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: C27H46O
#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
#6: 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

-
Details

Has ligand of interestY
Has protein modificationY

-
Experimental details

-
Experiment

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

-
Sample preparation

ComponentName: Multidrug resistance protein / 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
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 291 K

-
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: 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

-
Processing

EM software
IDNameVersionCategory
7Coot0.9.8.92model fitting
9RELION3.1initial Euler assignment
10RELION3.1final Euler assignment
12cryoSPARC4.2.13D reconstruction
13PHENIX1.20.1model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 2.54 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 101021 / 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: 118.7 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00298636
ELECTRON MICROSCOPYf_angle_d0.554811793
ELECTRON MICROSCOPYf_chiral_restr0.0381374
ELECTRON MICROSCOPYf_plane_restr0.00451389
ELECTRON MICROSCOPYf_dihedral_angle_d9.22841465

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more