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- EMDB-38987: P-glycoprotein in complex with UIC2 Fab and triple elacridar mole... -

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Basic information

Entry
Database: EMDB / ID: EMD-38987
TitleP-glycoprotein in complex with UIC2 Fab and triple elacridar molecules in nanodisc
Map data
Sample
  • Complex: Multidrug resistance protein
    • Protein or peptide: ATP-dependent translocase ABCB1,mNeonGreen
    • Protein or peptide: UIC2 Fab light chain
    • Protein or peptide: UIC2 Fab heavy chain
  • Ligand: CHOLESTEROL
  • Ligand: 1,2-Distearoyl-sn-glycerophosphoethanolamine
  • Ligand: elacridar
KeywordsABC transporter / elacridar / P-glycoprotein / MEMBRANE PROTEIN
Function / homology
Function and homology information


terpenoid transport / ceramide floppase activity / carboxylic acid transmembrane transport / phosphatidylethanolamine floppase activity / regulation of chloride transport / floppase activity / ceramide translocation / Abacavir transmembrane transport / carboxylic acid transmembrane transporter activity / phosphatidylethanolamine flippase activity ...terpenoid transport / ceramide floppase activity / carboxylic acid transmembrane transport / phosphatidylethanolamine floppase activity / regulation of chloride transport / floppase activity / ceramide translocation / Abacavir transmembrane transport / carboxylic acid transmembrane transporter activity / phosphatidylethanolamine flippase activity / xenobiotic transport across blood-brain barrier / stem cell proliferation / external side of apical plasma membrane / phosphatidylcholine floppase activity / 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 / ATPase-coupled transmembrane transporter activity / efflux transmembrane transporter activity / xenobiotic transmembrane transporter activity / transport across blood-brain barrier / transmembrane transporter activity / xenobiotic metabolic process / bioluminescence / G2/M transition of mitotic cell cycle / transmembrane transport / ABC-family protein mediated transport / 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
mNeonGreen / ATP-dependent translocase ABCB1
Similarity search - Component
Biological speciesHomo sapiens (human) / Mus musculus (house mouse)
Methodsingle 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, 3 items
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, 2024-
Header (metadata) releaseApr 17, 2024-
Map releaseApr 17, 2024-
UpdateNov 27, 2024-
Current statusNov 27, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_38987.png

Downloads & links

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Map

FileDownload / File: emd_38987.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 360 pix.
= 298.8 Å		0.83 Å/pix.
x 360 pix.
= 298.8 Å		0.83 Å/pix.
x 360 pix.
= 298.8 Å

Surface

Projections

Slices (1/3)

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Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.83 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.346
Minimum - Maximum-0.6625549 - 1.767262
Average (Standard dev.)-0.0001970924 (±0.040649947)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 298.8 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_38987_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_38987_half_map_2.map
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Sample components

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Entire : Multidrug resistance protein

EntireName: Multidrug resistance protein
Components
  • Complex: Multidrug resistance protein
    • Protein or peptide: ATP-dependent translocase ABCB1,mNeonGreen
    • Protein or peptide: UIC2 Fab light chain
    • Protein or peptide: UIC2 Fab heavy chain
  • Ligand: CHOLESTEROL
  • Ligand: 1,2-Distearoyl-sn-glycerophosphoethanolamine
  • Ligand: elacridar

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Supramolecule #1: Multidrug resistance protein

SupramoleculeName: Multidrug resistance protein / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: ATP-dependent translocase ABCB1,mNeonGreen

MacromoleculeName: ATP-dependent translocase ABCB1,mNeonGreen / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: ABC-type xenobiotic transporter
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 170.535812 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MDLEGDRNGG AKKKNFFKLN NKSEKDKKEK KPTVSVFSMF RYSNWLDKLY MVVGTLAAII HGAGLPLMML VFGEMTDIFA NAGNLEDLM SNITNRSDIN DTGFFMNLEE DMTRYAYYYS GIGAGVLVAA YIQVSFWCLA AGRQIHKIRK QFFHAIMRQE I GWFDVHDV ...String:
MDLEGDRNGG AKKKNFFKLN NKSEKDKKEK KPTVSVFSMF RYSNWLDKLY MVVGTLAAII HGAGLPLMML VFGEMTDIFA NAGNLEDLM SNITNRSDIN DTGFFMNLEE DMTRYAYYYS GIGAGVLVAA YIQVSFWCLA AGRQIHKIRK QFFHAIMRQE I GWFDVHDV GELNTRLTDD VSKINEGIGD KIGMFFQSMA TFFTGFIVGF TRGWKLTLVI LAISPVLGLS AAVWAKILSS FT DKELLAY AKAGAVAEEV LAAIRTVIAF GGQKKELERY NKNLEEAKRI GIKKAITANI SIGAAFLLIY ASYALAFWYG TTL VLSGEY SIGQVLTVFF SVLIGAFSVG QASPSIEAFA NARGAAYEIF KIIDNKPSID SYSKSGHKPD NIKGNLEFRN VHFS YPSRK EVKILKGLNL KVQSGQTVAL VGNSGCGKST TVQLMQRLYD PTEGMVSVDG QDIRTINVRF LREIIGVVSQ EPVLF ATTI AENIRYGREN VTMDEIEKAV KEANAYDFIM KLPHKFDTLV GERGAQLSGG QKQRIAIARA LVRNPKILLL DEATSA LDT ESEAVVQVAL DKARKGRTTI VIAHRLSTVR NADVIAGFDD GVIVEKGNHD ELMKEKGIYF KLVTMQTAGN EVELENA AD ESKSEIDALE MSSNDSRSSL IRKRSTRRSV RGSQAQDRKL STKEALDESI PPVSFWRIMK LNLTEWPYFV VGVFCAII N GGLQPAFAII FSKIIGVFTR IDDPETKRQN SNLFSLLFLA LGIISFITFF LQGFTFGKAG EILTKRLRYM VFRSMLRQD VSWFDDPKNT TGALTTRLAN DAAQVKGAIG SRLAVITQNI ANLGTGIIIS FIYGWQLTLL LLAIVPIIAI AGVVEMKMLS GQALKDKKE LEGSGKIATE AIENFRTVVS LTQEQKFEHM YAQSLQVPYR NSLRKAHIFG ITFSFTQAMM YFSYAGCFRF G AYLVAHKL MSFEDVLLVF SAVVFGAMAV GQVSSFAPDY AKAKISAAHI IMIIEKTPLI DSYSTEGLMP NTLEGNVTFG EV VFNYPTR PDIPVLQGLS LEVKKGQTLA LVGSSGCGKS TVVQLLERFY DPLAGKVLLD GKEIKRLNVQ WLRAHLGIVS QEP ILFDCS IAENIAYGDN SRVVSQEEIV RAAKEANIHA FIESLPNKYS TKVGDKGTQL SGGQKQRIAI ARALVRQPHI LLLD EATSA LDTESEKVVQ EALDKAREGR TCIVIAHRLS TIQNADLIVV FQNGRVKEHG THQQLLAQKG IYFSMVSVQA GTKRQ LEVL FQGPRPRGSK GEEDNMASLP ATHELHIFGS INGVDFDMVG QGTGNPNDGY EELNLKSTKG DLQFSPWILV PHIGYG FHQ YLPYPDGMSP FQAAMVDGSG YQVHRTMQFE DGASLTVNYR YTYEGSHIKG EAQVKGTGFP ADGPVMTNSL TAADWCR SK KTYPNDKTII STFKWSYTTG NGKRYRSTAR TTYTFAKPMA ANYLKNQPMY VFRKTELKHS KTELNFKEWQ KAFTDVMG M DELYKHHHHH HHH

UniProtKB: ATP-dependent translocase ABCB1, mNeonGreen

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Macromolecule #2: UIC2 Fab light chain

MacromoleculeName: UIC2 Fab light chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 24.321039 KDa
Recombinant expressionOrganism: Mus musculus (house mouse)
SequenceString: QVVMTQSPLS LPVSLGDQAS ISCRSSQSLL HSNGNTYLHW YLQKPGQSPK LLIYKVSNRF SGVPDRFSGS GSGTDFTLKI SRVEAEDLG VYFCSQSTHI PPWTFGGGTK LDIKRADAAP TVSIFPPSSE QLTSGGLSVV CFLNNFYPKD INVKWKIDGS E RQNGVLNS ...String:
QVVMTQSPLS LPVSLGDQAS ISCRSSQSLL HSNGNTYLHW YLQKPGQSPK LLIYKVSNRF SGVPDRFSGS GSGTDFTLKI SRVEAEDLG VYFCSQSTHI PPWTFGGGTK LDIKRADAAP TVSIFPPSSE QLTSGGLSVV CFLNNFYPKD INVKWKIDGS E RQNGVLNS WTDQDSKDST YSMSSTLTLT KDEYERHNSY TCEATHKTST SPIVKSFNRN EC

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Macromolecule #3: UIC2 Fab heavy chain

MacromoleculeName: UIC2 Fab heavy chain / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 24.381281 KDa
Recombinant expressionOrganism: Mus musculus (house mouse)
SequenceString: EVQLQESGPE LVKTGASVKI SCKASGYSFS NYYIHWVKQS HGKSLEWIGF ISCYNGATFY NQKFKGKATF TVDNSSSTAY MKFNSLTFE DSAVYYCARL PIQFGNFYPM DYWGQGTTVT VSSAKTTAPS VYPLAPVCGD TTGSSVTLGC LVKGYFPEPV T LTWNSGSL ...String:
EVQLQESGPE LVKTGASVKI SCKASGYSFS NYYIHWVKQS HGKSLEWIGF ISCYNGATFY NQKFKGKATF TVDNSSSTAY MKFNSLTFE DSAVYYCARL PIQFGNFYPM DYWGQGTTVT VSSAKTTAPS VYPLAPVCGD TTGSSVTLGC LVKGYFPEPV T LTWNSGSL SSGVHTFPAV LQSDLYTLSS SVTVTSSTWP SQSITCNVAH PASSTKVDKK IEPRGPT

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Macromolecule #4: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 4 / Number of copies: 12 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL

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Macromolecule #5: 1,2-Distearoyl-sn-glycerophosphoethanolamine

MacromoleculeName: 1,2-Distearoyl-sn-glycerophosphoethanolamine / type: ligand / ID: 5 / Number of copies: 1 / Formula: 3PE
Molecular weightTheoretical: 748.065 Da
Chemical component information

ChemComp-3PE:
1,2-Distearoyl-sn-glycerophosphoethanolamine / phospholipid*YM

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Macromolecule #6: elacridar

MacromoleculeName: elacridar / type: ligand / ID: 6 / Number of copies: 3 / Formula: R0Z
Molecular weightTheoretical: 563.643 Da
Chemical component information

ChemComp-R0Z:
elacridar

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 180 sec. / Pretreatment - Atmosphere: AIR
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 291 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Number grids imaged: 1 / Number real images: 4482 / Average electron dose: 48.8 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 20.0 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

6qex

Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 2.54 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.2.1) / Number images used: 101021
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 3.1)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 3.1)

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Atomic model buiding 1

Initial modelPDB ID:

6qex


Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementSpace: RECIPROCAL
Output model

PDB-8y6i:
P-glycoprotein in complex with UIC2 Fab and triple elacridar molecules in nanodisc

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