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- PDB-8f4b: Bovine multidrug resistance protein 1 (MRP1) bound to cyclic pept... -

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Basic information

Entry
Database: PDB / ID: 8f4b
TitleBovine multidrug resistance protein 1 (MRP1) bound to cyclic peptide inhibitor 1 (CPI1)
Components
  • Cyclic peptide inhibitor 1 (CPI1)
  • Multidrug resistance-associated protein 1
KeywordsTRANSPORT PROTEIN
Function / homology
Function and homology information


Heme degradation / Synthesis of Leukotrienes (LT) and Eoxins (EX) / cyclic nucleotide transport / Transport of RCbl within the body / Paracetamol ADME / leukotriene transport / glutathione transmembrane transporter activity / glutathione transmembrane transport / ABC-type glutathione-S-conjugate transporter / ABC-type glutathione S-conjugate transporter activity ...Heme degradation / Synthesis of Leukotrienes (LT) and Eoxins (EX) / cyclic nucleotide transport / Transport of RCbl within the body / Paracetamol ADME / leukotriene transport / glutathione transmembrane transporter activity / glutathione transmembrane transport / ABC-type glutathione-S-conjugate transporter / ABC-type glutathione S-conjugate transporter activity / ABC-family proteins mediated transport / Cytoprotection by HMOX1 / ABC-type xenobiotic transporter / ABC-type xenobiotic transporter activity / xenobiotic transport / lipid transport / xenobiotic transmembrane transporter activity / ABC-type transporter activity / positive regulation of inflammatory response / basolateral plasma membrane / response to xenobiotic stimulus / ATP hydrolysis activity / ATP binding
Similarity search - Function
Multi drug resistance-associated protein / 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. ...Multi drug resistance-associated protein / 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
: / Multidrug resistance-associated protein 1
Similarity search - Component
Biological speciesBos taurus (cattle)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.27 Å
AuthorsPietz, H.L. / Chen, J.
Funding support United States, 2items
OrganizationGrant numberCountry
Howard Hughes Medical Institute (HHMI) United States
National Institutes of Health/National Cancer Institute (NIH/NCI)5F30CA257282-03 United States
CitationJournal: Proc Natl Acad Sci U S A / Year: 2023
Title: A macrocyclic peptide inhibitor traps MRP1 in a catalytically incompetent conformation.
Authors: Harlan L Pietz / Ata Abbas / Zachary Lee Johnson / Michael L Oldham / Hiroaki Suga / Jue Chen /
Abstract: Adenosine triphosphate-binding cassette (ABC) transporters, such as multidrug resistance protein 1 (MRP1), protect against cellular toxicity by exporting xenobiotic compounds across the plasma ...Adenosine triphosphate-binding cassette (ABC) transporters, such as multidrug resistance protein 1 (MRP1), protect against cellular toxicity by exporting xenobiotic compounds across the plasma membrane. However, constitutive MRP1 function hinders drug delivery across the blood-brain barrier, and MRP1 overexpression in certain cancers leads to acquired multidrug resistance and chemotherapy failure. Small-molecule inhibitors have the potential to block substrate transport, but few show specificity for MRP1. Here we identify a macrocyclic peptide, named CPI1, which inhibits MRP1 with nanomolar potency but shows minimal inhibition of a related multidrug transporter P-glycoprotein. A cryoelectron microscopy (cryo-EM) structure at 3.27 Å resolution shows that CPI1 binds MRP1 at the same location as the physiological substrate leukotriene C4 (LTC). Residues that interact with both ligands contain large, flexible sidechains that can form a variety of interactions, revealing how MRP1 recognizes multiple structurally unrelated molecules. CPI1 binding prevents the conformational changes necessary for adenosine triphosphate (ATP) hydrolysis and substrate transport, suggesting it may have potential as a therapeutic candidate.
History
DepositionNov 10, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 22, 2023Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Multidrug resistance-associated protein 1
B: Cyclic peptide inhibitor 1 (CPI1)


Theoretical massNumber of molelcules
Total (without water)150,3322
Polymers150,3322
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Multidrug resistance-associated protein 1 / ATP-binding cassette sub-family C member 1 / Glutathione-S-conjugate-translocating ATPase ABCC1 / ...ATP-binding cassette sub-family C member 1 / Glutathione-S-conjugate-translocating ATPase ABCC1 / Leukotriene C(4) transporter / LTC4 transporter


Mass: 148045.859 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Bos taurus (cattle) / Gene: ABCC1, MRP1 / Production host: Homo sapiens (human)
References: UniProt: Q8HXQ5, ABC-type xenobiotic transporter, ABC-type glutathione-S-conjugate transporter
#2: Protein/peptide Cyclic peptide inhibitor 1 (CPI1)


Type: Peptide-like / Class: Inhibitor / Mass: 2286.456 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others) / Production host: synthetic construct (others) / References: BIRD: PRD_002516
Has ligand of interestN

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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: Bovine multidrug resistance protein 1 (MRP1) in complex with cyclic peptide inhibitor 1 (CPI1)
Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Bos taurus (cattle)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
SpecimenConc.: 4 mg/ml / Embedding 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 FIELDBright-field microscopy / Nominal defocus max: 2400 nm / Nominal defocus min: 700 nm
Image recordingAverage exposure time: 0.2 sec. / Electron dose: 1.5 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 3708
Image scansMovie frames/image: 50 / Used frames/image: 1-50

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Processing

SoftwareName: REFMAC / Version: 5.8.0267 / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.27 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 134960 / Symmetry type: POINT
Atomic model buildingProtocol: OTHER / Space: REAL
RefinementResolution: 3.27→146 Å / Cor.coef. Fo:Fc: 0.864 / SU B: 23.334 / SU ML: 0.368 / ESU R: 0.453
Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflection
Rwork0.36044 --
obs0.36044 95433 100 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 137.464 Å2
Baniso -1Baniso -2Baniso -3
1--1.28 Å2-1.56 Å20.16 Å2
2--0.95 Å20.52 Å2
3---0.33 Å2
Refinement stepCycle: 1 / Total: 9323
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
ELECTRON MICROSCOPYr_bond_refined_d0.0020.0139515
ELECTRON MICROSCOPYr_bond_other_d0.0010.0159333
ELECTRON MICROSCOPYr_angle_refined_deg1.2481.62612903
ELECTRON MICROSCOPYr_angle_other_deg1.0221.57121426
ELECTRON MICROSCOPYr_dihedral_angle_1_deg4.93451178
ELECTRON MICROSCOPYr_dihedral_angle_2_deg29.17422.027449
ELECTRON MICROSCOPYr_dihedral_angle_3_deg12.947151684
ELECTRON MICROSCOPYr_dihedral_angle_4_deg12.4491556
ELECTRON MICROSCOPYr_chiral_restr0.0440.21248
ELECTRON MICROSCOPYr_gen_planes_refined0.0030.0210570
ELECTRON MICROSCOPYr_gen_planes_other0.0010.022182
ELECTRON MICROSCOPYr_nbd_refined
ELECTRON MICROSCOPYr_nbd_other
ELECTRON MICROSCOPYr_nbtor_refined
ELECTRON MICROSCOPYr_nbtor_other
ELECTRON MICROSCOPYr_xyhbond_nbd_refined
ELECTRON MICROSCOPYr_xyhbond_nbd_other
ELECTRON MICROSCOPYr_metal_ion_refined
ELECTRON MICROSCOPYr_metal_ion_other
ELECTRON MICROSCOPYr_symmetry_vdw_refined
ELECTRON MICROSCOPYr_symmetry_vdw_other
ELECTRON MICROSCOPYr_symmetry_hbond_refined
ELECTRON MICROSCOPYr_symmetry_hbond_other
ELECTRON MICROSCOPYr_symmetry_metal_ion_refined
ELECTRON MICROSCOPYr_symmetry_metal_ion_other
ELECTRON MICROSCOPYr_mcbond_it4.48214.4974724
ELECTRON MICROSCOPYr_mcbond_other4.48214.4964723
ELECTRON MICROSCOPYr_mcangle_it7.26621.775898
ELECTRON MICROSCOPYr_mcangle_other7.26521.7725899
ELECTRON MICROSCOPYr_scbond_it4.12814.94791
ELECTRON MICROSCOPYr_scbond_other4.12714.9014792
ELECTRON MICROSCOPYr_scangle_it
ELECTRON MICROSCOPYr_scangle_other7.09722.1387006
ELECTRON MICROSCOPYr_long_range_B_refined11.12311084
ELECTRON MICROSCOPYr_long_range_B_other11.12211085
ELECTRON MICROSCOPYr_rigid_bond_restr
ELECTRON MICROSCOPYr_sphericity_free
ELECTRON MICROSCOPYr_sphericity_bonded
LS refinement shellResolution: 3.14→3.222 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0 0 -
Rwork0.537 7077 -
obs--100 %

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