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- EMDB-35836: cryo-EM structure of PGE1-bound hMRP4 -

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Basic information

Entry
Database: EMDB / ID: EMD-35836
Titlecryo-EM structure of PGE1-bound hMRP4
Map data
Sample
  • Complex: PGE1-bound hMRP4
    • Protein or peptide: ATP-binding cassette sub-family C member 4
  • Ligand: 7-[(1R,3R)-3-hydroxy-2-[(1E,3S)-3-hydroxyoct-1-en-1-yl]-5-oxocyclopentyl]heptanoic acid
Keywordscryo-EM structure of PGE1-bound hMRP4 / MEMBRANE PROTEIN
Function / homology
Function and homology information


15-hydroxyprostaglandin dehydrogenase (NAD+) activity / purine nucleotide transmembrane transporter activity / cAMP transport / guanine nucleotide transmembrane transporter activity / ABC-type bile acid transporter activity / platelet dense granule membrane / platelet degranulation / prostaglandin transport / leukotriene transport / prostaglandin transmembrane transporter activity ...15-hydroxyprostaglandin dehydrogenase (NAD+) activity / purine nucleotide transmembrane transporter activity / cAMP transport / guanine nucleotide transmembrane transporter activity / ABC-type bile acid transporter activity / platelet dense granule membrane / platelet degranulation / prostaglandin transport / leukotriene transport / prostaglandin transmembrane transporter activity / ABC-type glutathione-S-conjugate transporter / ABC-type glutathione S-conjugate transporter activity / urate transport / glutathione transmembrane transporter activity / urate transmembrane transporter activity / ATPase-coupled inorganic anion transmembrane transporter activity / external side of apical plasma membrane / xenobiotic transmembrane transport / prostaglandin secretion / export across plasma membrane / Paracetamol ADME / ABC-type xenobiotic transporter / Translocases; Catalysing the translocation of other compounds; Linked to the hydrolysis of a nucleoside triphosphate / Azathioprine ADME / ABC-type xenobiotic transporter activity / bile acid and bile salt transport / efflux transmembrane transporter activity / xenobiotic transmembrane transporter activity / cilium assembly / ATPase-coupled transmembrane transporter activity / ABC-type transporter activity / transport across blood-brain barrier / xenobiotic metabolic process / ABC-family proteins mediated transport / transmembrane transport / Platelet degranulation / basolateral plasma membrane / apical plasma membrane / intracellular membrane-bounded organelle / nucleolus / Golgi apparatus / ATP hydrolysis activity / ATP binding / membrane / plasma membrane
Similarity search - Function
ATP-binding cassette sub-family C member 4 / : / : / 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 ...ATP-binding cassette sub-family C member 4 / : / : / 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
ATP-binding cassette sub-family C member 4
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.95 Å
AuthorsLiu ZM / Huang Y
Funding support China, 1 items
OrganizationGrant numberCountry
National Science Foundation (NSF, China) China
CitationJournal: Commun Biol / Year: 2023
Title: Structural basis for substrate and inhibitor recognition of human multidrug transporter MRP4.
Authors: Ying Huang / Chenyang Xue / Liangdong Wang / Ruiqian Bu / Jianqiang Mu / Yong Wang / Zhongmin Liu /
Abstract: Human multidrug resistance protein 4 (hMRP4, also known as ABCC4), with a representative topology of the MRP subfamily, translocates various substrates across the membrane and contributes to the ...Human multidrug resistance protein 4 (hMRP4, also known as ABCC4), with a representative topology of the MRP subfamily, translocates various substrates across the membrane and contributes to the development of multidrug resistance. However, the underlying transport mechanism of hMRP4 remains unclear due to a lack of high-resolution structures. Here, we use cryogenic electron microscopy (cryo-EM) to resolve its near-atomic structures in the apo inward-open and the ATP-bound outward-open states. We also capture the PGE1 substrate-bound structure and, importantly, the inhibitor-bound structure of hMRP4 in complex with sulindac, revealing that substrate and inhibitor compete for the same hydrophobic binding pocket although with different binding modes. Moreover, our cryo-EM structures, together with molecular dynamics simulations and biochemical assay, shed light on the structural basis of the substrate transport and inhibition mechanism, with implications for the development of hMRP4-targeted drugs.
History
DepositionApr 6, 2023-
Header (metadata) releaseApr 10, 2024-
Map releaseApr 10, 2024-
UpdateOct 23, 2024-
Current statusOct 23, 2024Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_35836.png

Downloads & links

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Map

FileDownload / File: emd_35836.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.86 Å/pix.
x 300 pix.
= 256.5 Å		0.86 Å/pix.
x 300 pix.
= 256.5 Å		0.86 Å/pix.
x 300 pix.
= 256.5 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.855 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.2
Minimum - Maximum-2.5832257 - 3.5402186
Average (Standard dev.)0.0039047454 (±0.074857)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 256.5 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_35836_half_map_1.map
Projections & Slices
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Histogram

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Half map: #1

Fileemd_35836_half_map_2.map
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Sample components

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Entire : PGE1-bound hMRP4

EntireName: PGE1-bound hMRP4
Components
  • Complex: PGE1-bound hMRP4
    • Protein or peptide: ATP-binding cassette sub-family C member 4
  • Ligand: 7-[(1R,3R)-3-hydroxy-2-[(1E,3S)-3-hydroxyoct-1-en-1-yl]-5-oxocyclopentyl]heptanoic acid

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Supramolecule #1: PGE1-bound hMRP4

SupramoleculeName: PGE1-bound hMRP4 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: ATP-binding cassette sub-family C member 4

MacromoleculeName: ATP-binding cassette sub-family C member 4 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
EC number: Translocases; Catalysing the translocation of other compounds; Linked to the hydrolysis of a nucleoside triphosphate
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 153.171359 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MLPVYQEVKP NPLQDANLCS RVFFWWLNPL FKIGHKRRLE EDDMYSVLPE DRSQHLGEEL QGFWDKEVLR AENDAQKPSL TRAIIKCYW KSYLVLGIFT LIEESAKVIQ PIFLGKIINY FENYDPMDSV ALNTAYAYAT VLTFCTLILA ILHHLYFYHV Q CAGMRLRV ...String:
MLPVYQEVKP NPLQDANLCS RVFFWWLNPL FKIGHKRRLE EDDMYSVLPE DRSQHLGEEL QGFWDKEVLR AENDAQKPSL TRAIIKCYW KSYLVLGIFT LIEESAKVIQ PIFLGKIINY FENYDPMDSV ALNTAYAYAT VLTFCTLILA ILHHLYFYHV Q CAGMRLRV AMCHMIYRKA LRLSNMAMGK TTTGQIVNLL SNDVNKFDQV TVFLHFLWAG PLQAIAVTAL LWMEIGISCL AG MAVLIIL LPLQSCFGKL FSSLRSKTAT FTDARIRTMN EVITGIRIIK MYAWEKSFSN LITNLRKKEI SKILRSSCLR GMN LASFFS ASKIIVFVTF TTYVLLGSVI TASRVFVAVT LYGAVRLTVT LFFPSAIERV SEAIVSIRRI QTFLLLDEIS QRNR QLPSD GKKMVHVQDF TAFWDKASET PTLQGLSFTV RPGELLAVVG PVGAGKSSLL SAVLGELAPS HGLVSVHGRI AYVSQ QPWV FSGTLRSNIL FGKKYEKERY EKVIKACALK KDLQLLEDGD LTVIGDRGTT LSGGQKARVN LARAVYQDAD IYLLDD PLS AVDAEVSRHL FELCICQILH EKITILVTHQ LQYLKAASQI LILKDGKMVQ KGTYTEFLKS GIDFGSLLKK DNEESEQ PP VPGTPTLRNR TFSESSVWSQ QSSRPSLKDG ALESQDTENV PVTLSEENRS EGKVGFQAYK NYFRAGAHWI VFIFLILL N TAAQVAYVLQ DWWLSYWANK QSMLNVTVNG GGNVTEKLDL NWYLGIYSGL TVATVLFGIA RSLLVFYVLV NSSQTLHNK MFESILKAPV LFFDRNPIGR ILNRFSKDIG HLDDLLPLTF LDFIQTLLQV VGVVSVAVAV IPWIAIPLVP LGIIFIFLRR YFLETSRDV KRLESTTRSP VFSHLSSSLQ GLWTIRAYKA EERCQELFDA HQDLHSEAWF LFLTTSRWFA VRLDAICAMF V IIVAFGSL ILAKTLDAGQ VGLALSYALT LMGMFQWCVR QSAEVENMMI SVERVIEYTD LEKEAPWEYQ KRPPPAWPHE GV IIFDNVN FMYSPGGPLV LKHLTALIKS QEKVGIVGRT GAGKSSLISA LFRLSEPEGK IWIDKILTTE IGLHDLRKKM SII PQEPVL FTGTMRKNLD PFNEHTDEEL WNALQEVQLK ETIEDLPGKM DTELAESGSN FSVGQRQLVC LARAILRKNQ ILII DEATA NVDPRTDELI QKKIREKFAH CTVLTIAHRL NTIIDSDKIM VLDSGRLKEY DEPYVLLQNK ESLFYKMVQQ LGKAE AAAL TETAKQVYFK RNYPHIGHTD HMVTNTSNGQ PSTLTIFETA LLEGGGSGGG SDYKDHDGDY KDHDIDYKDD DDK

UniProtKB: ATP-binding cassette sub-family C member 4

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Macromolecule #2: 7-[(1R,3R)-3-hydroxy-2-[(1E,3S)-3-hydroxyoct-1-en-1-yl]-5-oxocycl...

MacromoleculeName: 7-[(1R,3R)-3-hydroxy-2-[(1E,3S)-3-hydroxyoct-1-en-1-yl]-5-oxocyclopentyl]heptanoic acid
type: ligand / ID: 2 / Number of copies: 1 / Formula: XPG
Molecular weightTheoretical: 354.481 Da
Chemical component information

ChemComp-XPG:
7-[(1R,3R)-3-hydroxy-2-[(1E,3S)-3-hydroxyoct-1-en-1-yl]-5-oxocyclopentyl]heptanoic acid / medication*YM

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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

BufferpH: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.8 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.95 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 378698
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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