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Yorodumi- EMDB-28854: Bovine multidrug resistance protein 1 (MRP1) bound to cyclic pept... -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-28854 | |||||||||
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Title | Bovine multidrug resistance protein 1 (MRP1) bound to cyclic peptide inhibitor 1 (CPI1) | |||||||||
Map data | Full map of the 3.27 angstrom density map generated from image processing in RELION | |||||||||
Sample |
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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 transport / glutathione transmembrane transporter activity / ABC-type glutathione-S-conjugate transporter ...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 transport / glutathione transmembrane transporter activity / 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 / xenobiotic transport / ABC-type xenobiotic transporter activity / 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 | single particle reconstruction / cryo EM / Resolution: 3.27 Å | |||||||||
Authors | Pietz HL / Chen J | |||||||||
Funding support | United States, 2 items
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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
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_28854.map.gz | 117 MB | EMDB map data format | |
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Header (meta data) | emd-28854-v30.xml emd-28854.xml | 25.6 KB 25.6 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_28854_fsc.xml | 11.4 KB | Display | FSC data file |
Images | emd_28854.png | 126.4 KB | ||
Masks | emd_28854_msk_1.map | 125 MB | Mask map | |
Others | emd_28854_additional_1.map.gz emd_28854_additional_2.map.gz emd_28854_additional_3.map.gz emd_28854_additional_4.map.gz emd_28854_half_map_1.map.gz emd_28854_half_map_2.map.gz | 4.7 MB 4.7 MB 4.7 MB 6.8 MB 98.3 MB 98.3 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-28854 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-28854 | HTTPS FTP |
-Validation report
Summary document | emd_28854_validation.pdf.gz | 790.8 KB | Display | EMDB validaton report |
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Full document | emd_28854_full_validation.pdf.gz | 790.3 KB | Display | |
Data in XML | emd_28854_validation.xml.gz | 18.3 KB | Display | |
Data in CIF | emd_28854_validation.cif.gz | 23.9 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-28854 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-28854 | HTTPS FTP |
-Related structure data
Related structure data | 8f4bMC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_28854.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
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Annotation | Full map of the 3.27 angstrom density map generated from image processing in RELION | ||||||||||||||||||||
Voxel size | X=Y=Z: 1.03 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Mask #1
File | emd_28854_msk_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Additional map: Full density-modified map from the 3.27 angstrom map...
File | emd_28854_additional_1.map | ||||||||||||
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Annotation | Full density-modified map from the 3.27 angstrom map generated from image processing in RELION | ||||||||||||
Projections & Slices |
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Density Histograms |
-Additional map: First half map of density-modified map from 3.27...
File | emd_28854_additional_2.map | ||||||||||||
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Annotation | First half map of density-modified map from 3.27 angstrom map generated from image processing in RELION | ||||||||||||
Projections & Slices |
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Density Histograms |
-Additional map: Second half map of density-modified map from 3.27...
File | emd_28854_additional_3.map | ||||||||||||
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Annotation | Second half map of density-modified map from 3.27 angstrom map generated from image processing in RELION | ||||||||||||
Projections & Slices |
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Density Histograms |
-Additional map: Masked full map of the 3.27 angstrom density...
File | emd_28854_additional_4.map | ||||||||||||
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Annotation | Masked full map of the 3.27 angstrom density map generated from image processing in RELION | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: Second half map of the 3.27 angstrom density...
File | emd_28854_half_map_1.map | ||||||||||||
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Annotation | Second half map of the 3.27 angstrom density map generated from image processing in RELION | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: First half map of the 3.27 angstrom density...
File | emd_28854_half_map_2.map | ||||||||||||
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Annotation | First half map of the 3.27 angstrom density map generated from image processing in RELION | ||||||||||||
Projections & Slices |
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Density Histograms |
-Sample components
-Entire : Bovine multidrug resistance protein 1 (MRP1) in complex with cycl...
Entire | Name: Bovine multidrug resistance protein 1 (MRP1) in complex with cyclic peptide inhibitor 1 (CPI1) |
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Components |
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-Supramolecule #1: Bovine multidrug resistance protein 1 (MRP1) in complex with cycl...
Supramolecule | Name: Bovine multidrug resistance protein 1 (MRP1) in complex with cyclic peptide inhibitor 1 (CPI1) type: complex / ID: 1 / Parent: 0 / Macromolecule list: all |
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Source (natural) | Organism: Bos taurus (cattle) |
-Macromolecule #1: Multidrug resistance-associated protein 1
Macromolecule | Name: Multidrug resistance-associated protein 1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: ABC-type xenobiotic transporter |
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Source (natural) | Organism: Bos taurus (cattle) |
Molecular weight | Theoretical: 148.045859 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: 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 |
-Macromolecule #2: Cyclic peptide inhibitor 1 (CPI1)
Macromolecule | Name: Cyclic peptide inhibitor 1 (CPI1) / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: synthetic construct (others) |
Molecular weight | Theoretical: 2.286456 KDa |
Recombinant expression | Organism: synthetic construct (others) |
Sequence | String: (DTY)FWGNLHWYY EQFDSTC(ACE) |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Concentration | 4 mg/mL |
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Buffer | pH: 8 |
Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film 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 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.4 µm / Nominal defocus min: 0.7000000000000001 µm |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
+Image processing
-Atomic model buiding 1
Refinement | Space: REAL / Protocol: OTHER |
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Output model | PDB-8f4b: |