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- PDB-9cr8: SapNP reconstituted human ABCB1 -

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Basic information

Entry
Database: PDB / ID: 9cr8
TitleSapNP reconstituted human ABCB1
ComponentsATP-dependent translocase ABCB1
KeywordsMEMBRANE PROTEIN / TRANSLOCASE / ABCB1 / P-gp / apo form / nanoparticle / saposin A / MDR1 / p-glycoprotein / pgp
Function / homology
Function and homology information


carboxylic acid transmembrane transport / carboxylic acid transmembrane transporter activity / terpenoid transport / ceramide floppase activity / ceramide translocation / floppase activity / Abacavir transmembrane transport / external side of apical plasma membrane / phosphatidylethanolamine flippase activity / phosphatidylcholine floppase activity ...carboxylic acid transmembrane transport / carboxylic acid transmembrane transporter activity / terpenoid transport / ceramide floppase activity / ceramide translocation / floppase activity / Abacavir transmembrane transport / external side of apical plasma membrane / phosphatidylethanolamine flippase activity / phosphatidylcholine floppase activity / Atorvastatin ADME / xenobiotic detoxification by transmembrane export across the plasma membrane / xenobiotic transport across blood-brain barrier / transepithelial transport / export across plasma membrane / P-type phospholipid transporter / ABC-type xenobiotic transporter / ABC-type xenobiotic transporter activity / phospholipid translocation / Prednisone ADME / efflux transmembrane transporter activity / transmembrane transporter activity / xenobiotic transmembrane transporter activity / ATPase-coupled transmembrane transporter activity / transport across blood-brain barrier / xenobiotic metabolic process / regulation of chloride transport / stem cell proliferation / ABC-family proteins mediated transport / transmembrane transport / G2/M transition of mitotic cell cycle / 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
UNKNOWN BRANCHED FRAGMENT OF PHOSPHOLIPID / ATP-dependent translocase ABCB1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.8 Å
AuthorsKurre, D. / Alam, A.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)1R01GM146906 United States
CitationJournal: EMBO J / Year: 2025
Title: Structural insights into binding-site access and ligand recognition by human ABCB1.
Authors: Devanshu Kurre / Phuoc X Dang / Le T M Le / Varun V Gadkari / Amer Alam /
Abstract: ABCB1 is a broad-spectrum efflux pump central to cellular drug handling and multidrug resistance in humans. However, how it is able to recognize and transport a wide range of diverse substrates ...ABCB1 is a broad-spectrum efflux pump central to cellular drug handling and multidrug resistance in humans. However, how it is able to recognize and transport a wide range of diverse substrates remains poorly understood. Here we present cryo-EM structures of lipid-embedded human ABCB1 in conformationally distinct apo-, substrate-bound, inhibitor-bound, and nucleotide-trapped states at 3.4-3.9 Å resolution, in the absence of stabilizing antibodies or mutations. The substrate-binding site is located within one half of the molecule and, in the apo state, is obstructed by the transmembrane helix (TM) 4. Substrate and inhibitor binding are distinguished by major TM rearrangements and their ligand binding chemistry, with TM4 playing a central role in all conformational transitions. Furthermore, our data identify secondary structure-breaking residues that impart localized TM flexibility and asymmetry between the two transmembrane domains. The resulting structural changes and lipid interactions that are induced by substrate and inhibitor binding can predict substrate-binding profiles and may direct ABCB1 inhibitor design.
History
DepositionJul 21, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 22, 2025Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: ATP-dependent translocase ABCB1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)148,82916
Polymers141,6451
Non-polymers7,18415
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein ATP-dependent translocase ABCB1 / 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: 141644.781 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: full length Human ABCB1 / Source: (gene. exp.) Homo sapiens (human) / Gene: ABCB1, MDR1, PGY1 / Cell (production host): T-REx-293 / Production host: Homo sapiens (human)
References: UniProt: P08183, ABC-type xenobiotic transporter, P-type phospholipid transporter
#2: Chemical
ChemComp-UPL / UNKNOWN BRANCHED FRAGMENT OF PHOSPHOLIPID / UNKNOWN PHOSPHOLIPID FRAGMENT


Mass: 478.920 Da / Num. of mol.: 15 / Source method: obtained synthetically / Formula: C34H70 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationN

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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: SapNP reconstituted human ABCB1 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human) / Cell: T-REx 293
Buffer solutionpH: 7.5 / Details: 25mM HEPES (pH 7.5), 150mM NaCl
Buffer component
IDConc.NameFormulaBuffer-ID
125 mM4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid1
2150 mMsodium chlorideNaCl1
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Details: Human ABCB1 reconstituted in Saposin A nanoparticles (SapNPs) comprising Brain Polar Lipids and Cholesterol
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: 95 % / Chamber temperature: 277 K

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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 / Nominal defocus max: 2500 nm / Nominal defocus min: 500 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 BIOCONTINUUM (6k x 4k)

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Processing

EM software
IDNameCategory
1RELIONparticle selection
2EPUimage acquisition
4RELIONCTF correction
8PHENIXmodel refinement
10RELIONinitial Euler assignment
12RELIONclassification
13RELION3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 660276 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0038806
ELECTRON MICROSCOPYf_angle_d0.49111816
ELECTRON MICROSCOPYf_dihedral_angle_d12.5423285
ELECTRON MICROSCOPYf_chiral_restr0.0391348
ELECTRON MICROSCOPYf_plane_restr0.0041465

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