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- EMDB-28854: Bovine multidrug resistance protein 1 (MRP1) bound to cyclic pept... -

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Basic information

Entry
Database: EMDB / ID: EMD-28854
TitleBovine multidrug resistance protein 1 (MRP1) bound to cyclic peptide inhibitor 1 (CPI1)
Map dataFull map of the 3.27 angstrom density map generated from image processing in RELION
Sample
  • Complex: Bovine multidrug resistance protein 1 (MRP1) in complex with cyclic peptide inhibitor 1 (CPI1)
    • Protein or peptide: Multidrug resistance-associated protein 1
    • Protein or peptide: Cyclic peptide inhibitor 1 (CPI1)
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)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.27 Å
AuthorsPietz HL / Chen J
Funding support United States, 2 items
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, 2022-
Header (metadata) releaseMar 22, 2023-
Map releaseMar 22, 2023-
UpdateMar 22, 2023-
Current statusMar 22, 2023Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_28854.png

Downloads & links

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Map

FileDownload / File: emd_28854.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationFull map of the 3.27 angstrom density map generated from image processing in RELION
Voxel sizeX=Y=Z: 1.03 Å
Density
Contour LevelBy AUTHOR: 0.0125
Minimum - Maximum-0.093823195 - 0.15400808
Average (Standard dev.)-4.4702238e-06 (±0.0032600667)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 329.59998 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_28854_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
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Histogram (log scale)

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Additional map: Full density-modified map from the 3.27 angstrom map...

Fileemd_28854_additional_1.map
AnnotationFull density-modified map from the 3.27 angstrom map generated from image processing in RELION
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Additional map: First half map of density-modified map from 3.27...

Fileemd_28854_additional_2.map
AnnotationFirst half map of density-modified map from 3.27 angstrom map generated from image processing in RELION
Projections & Slices
AxesZYX

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Histogram

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Additional map: Second half map of density-modified map from 3.27...

Fileemd_28854_additional_3.map
AnnotationSecond half map of density-modified map from 3.27 angstrom map generated from image processing in RELION
Projections & Slices
AxesZYX

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Histogram

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Additional map: Masked full map of the 3.27 angstrom density...

Fileemd_28854_additional_4.map
AnnotationMasked full map of the 3.27 angstrom density map generated from image processing in RELION
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Half map: Second half map of the 3.27 angstrom density...

Fileemd_28854_half_map_1.map
AnnotationSecond half map of the 3.27 angstrom density map generated from image processing in RELION
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: First half map of the 3.27 angstrom density...

Fileemd_28854_half_map_2.map
AnnotationFirst half map of the 3.27 angstrom density map generated from image processing in RELION
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Bovine multidrug resistance protein 1 (MRP1) in complex with cycl...

EntireName: Bovine multidrug resistance protein 1 (MRP1) in complex with cyclic peptide inhibitor 1 (CPI1)
Components
  • Complex: Bovine multidrug resistance protein 1 (MRP1) in complex with cyclic peptide inhibitor 1 (CPI1)
    • Protein or peptide: Multidrug resistance-associated protein 1
    • Protein or peptide: Cyclic peptide inhibitor 1 (CPI1)

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Supramolecule #1: Bovine multidrug resistance protein 1 (MRP1) in complex with cycl...

SupramoleculeName: Bovine multidrug resistance protein 1 (MRP1) in complex with cyclic peptide inhibitor 1 (CPI1)
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Bos taurus (cattle)

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Macromolecule #1: Multidrug resistance-associated protein 1

MacromoleculeName: Multidrug resistance-associated protein 1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: ABC-type xenobiotic transporter
Source (natural)Organism: Bos taurus (cattle)
Molecular weightTheoretical: 148.045859 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: PNPCPESSAS FLSRITFWWI TGMMVQGYRQ PLESTDLWSL NKEDTSEQVV PVLVKNWKKE CAKSRKQPVK IVYSSKDPAK PKGSSKVDV NEEAEALIVK CPQKERDPSL FKVLYKTFGP YFLMSFLFKA VHDLMMFAGP EILKLLINFV NDKKAPEWQG Y FYTALLFI ...String:
PNPCPESSAS FLSRITFWWI TGMMVQGYRQ PLESTDLWSL NKEDTSEQVV PVLVKNWKKE CAKSRKQPVK IVYSSKDPAK PKGSSKVDV NEEAEALIVK CPQKERDPSL FKVLYKTFGP YFLMSFLFKA VHDLMMFAGP EILKLLINFV NDKKAPEWQG Y FYTALLFI SACLQTLVLH QYFHICFVSG MRIKTAVIGA VYRKALVITN AARKSSTVGE IVNLMSVDAQ RFMDLATYIN MI WSAPLQV ILALYLLWLN LGPSVLAGVA VMVLMVPLNA VMAMKTKTYQ VAHMKSKDNR IKLMNEILNG IKVLKLYAWE LAF KDKVLA IRQEELKVLK KSAYLAAVGT FTWVCTPFLV ALSTFAVYVT VDENNILDAQ KAFVSLALFN ILRFPLNILP MVIS SIVQA SVSLKRLRVF LSHEDLDPDS IQRRPIKDAG ATNSITVKNA TFTWARNDPP TLHGITFSVP EGSLVAVVGQ VGCGK SSLL SALLAEMDKV EGHVTVKGSV AYVPQQAWIQ NISLRENILF GRQLQERYYK AVVEACALLP DLEILPSGDR TEIGEK GVN LSGGQKQRVS LARAVYCDSD VYLLDDPLSA VDAHVGKHIF ENVIGPKGLL KNKTRLLVTH AISYLPQMDV IIVMSGG KI SEMGSYQELL ARDGAFAEFL RTYASAEQEQ GQPEDGLAGV GGPGKEVKQM ENGMLVTDTA GKQMQRQLSS SSSYSRDV S QHHTSTAELR KPGPTEETWK LVEADKAQTG QVKLSVYWDY MKAIGLFISF LSIFLFLCNH VASLVSNYWL SLWTDDPIV NGTQEHTQVR LSVYGALGIS QGITVFGYSM AVSIGGIFAS RRLHLDLLHN VLRSPISFFE RTPSGNLVNR FSKELDTVDS MIPQVIKMF MGSLFNVIGA CIIILLATPM AAVIIPPLGL IYFFVQRFYV ASSRQLKRLE SVSRSPVYSH FNETLLGVSV I RAFEEQER FIRQSDLKVD ENQKAYYPSI VANRWLAVRL ECVGNCIVLF ASLFAVISRH SLSAGLVGLS VSYSLQVTTY LN WLVRMSS EMETNIVAVE RLKEYSETEK EAPWQIQDMA PPKDWPQVGR VEFRDYGLRY REDLDLVLKH INVTIDGGEK VGI VGRTGA GKSSLTLGLF RIKESAEGEI IIDDINIAKI GLHDLRFKIT IIPQDPVLFS GSLRMNLDPF SQYSDEEVWT SLEL AHLKG FVSALPDKLN HECAEGGENL SVGQRQLVCL ARALLRKTKI LVLDEATAAV DLETDDLIQS TIRTQFDDCT VLTIA HRLN TIMDYTRVIV LDKGEIQEWG SPSDLLQQRG LFYSMAKDSG LV

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Macromolecule #2: Cyclic peptide inhibitor 1 (CPI1)

MacromoleculeName: Cyclic peptide inhibitor 1 (CPI1) / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 2.286456 KDa
Recombinant expressionOrganism: synthetic construct (others)
SequenceString:
(DTY)FWGNLHWYY EQFDSTC(ACE)

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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

Concentration4 mg/mL
BufferpH: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.4 µm / Nominal defocus min: 0.7000000000000001 µm
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Digitization - Frames/image: 1-50 / Number grids imaged: 1 / Number real images: 3708 / Average exposure time: 0.2 sec. / Average electron dose: 1.5 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER / Details: Ab initio
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.27 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 134960
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: OTHER
Output model

PDB-8f4b:
Bovine multidrug resistance protein 1 (MRP1) bound to cyclic peptide inhibitor 1 (CPI1)

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