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Yorodumi- PDB-8f4b: Bovine multidrug resistance protein 1 (MRP1) bound to cyclic pept... -
+Open data
-Basic information
Entry | Database: PDB / ID: 8f4b | |||||||||
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Title | Bovine multidrug resistance protein 1 (MRP1) bound to cyclic peptide inhibitor 1 (CPI1) | |||||||||
Components |
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Keywords | TRANSPORT PROTEIN | |||||||||
Function / homology | Function and homology information Sphingolipid de novo biosynthesis / 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 / ABC-type glutathione-S-conjugate transporter / ABC-type glutathione S-conjugate transporter activity ...Sphingolipid de novo biosynthesis / 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 / ABC-type glutathione-S-conjugate transporter / ABC-type glutathione S-conjugate transporter activity / glutathione transmembrane transport / 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 | |||||||||
Biological species | Bos taurus (cattle) synthetic construct (others) | |||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.27 Å | |||||||||
Authors | Pietz, H.L. / Chen, J. | |||||||||
Funding support | United States, 2items
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Citation | Journal: 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 |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8f4b.cif.gz | 245.6 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8f4b.ent.gz | 193.5 KB | Display | PDB format |
PDBx/mmJSON format | 8f4b.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 8f4b_validation.pdf.gz | 1.1 MB | Display | wwPDB validaton report |
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Full document | 8f4b_full_validation.pdf.gz | 1.1 MB | Display | |
Data in XML | 8f4b_validation.xml.gz | 46.1 KB | Display | |
Data in CIF | 8f4b_validation.cif.gz | 68.7 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/f4/8f4b ftp://data.pdbj.org/pub/pdb/validation_reports/f4/8f4b | HTTPS FTP |
-Related structure data
Related structure data | 28854MC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
#1: Protein | 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 |
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#2: Protein/peptide | 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 interest | N |
-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: Bovine multidrug resistance protein 1 (MRP1) in complex with cyclic peptide inhibitor 1 (CPI1) Type: COMPLEX / Entity ID: all / Source: RECOMBINANT |
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Source (natural) | Organism: Bos taurus (cattle) |
Source (recombinant) | Organism: Homo sapiens (human) |
Buffer solution | pH: 8 |
Specimen | Conc.: 4 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 2400 nm / Nominal defocus min: 700 nm |
Image recording | Average 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 scans | Movie frames/image: 50 / Used frames/image: 1-50 |
-Processing
Software | Name: REFMAC / Version: 5.8.0267 / Classification: refinement | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
3D reconstruction | Resolution: 3.27 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 134960 / Symmetry type: POINT | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Atomic model building | Protocol: OTHER / Space: REAL | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Refinement | Resolution: 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
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Solvent computation | Ion probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Displacement parameters | Biso mean: 137.464 Å2
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Refinement step | Cycle: 1 / Total: 9323 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Refine LS restraints |
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