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- EMDB-37558: M5PI-bound hMRP5 -

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Basic information

Entry
Database: EMDB / ID: EMD-37558
TitleM5PI-bound hMRP5
Map data
Sample
  • Complex: M5PI-bound hMRP5
    • Protein or peptide: ATP-binding cassette sub-family C member 5
    • Protein or peptide: ATP-binding cassette sub-family C member 5
KeywordsM5PI-bound hMRP5 / MEMBRANE PROTEIN
Function / homology
Function and homology information


purine nucleotide transport / macromolecule transmembrane transporter activity / cGMP transport / carbohydrate derivative transmembrane transporter activity / Hyaluronan biosynthesis and export / folate transmembrane transport / purine nucleotide transmembrane transporter activity / cAMP transport / heme transmembrane transport / glutathione transmembrane transporter activity ...purine nucleotide transport / macromolecule transmembrane transporter activity / cGMP transport / carbohydrate derivative transmembrane transporter activity / Hyaluronan biosynthesis and export / folate transmembrane transport / purine nucleotide transmembrane transporter activity / cAMP transport / heme transmembrane transport / glutathione transmembrane transporter activity / heme transmembrane transporter activity / glutathione transmembrane transport / hyaluronan biosynthetic process / ATPase-coupled inorganic anion transmembrane transporter activity / xenobiotic transmembrane transport / organic anion transmembrane transporter activity / export across plasma membrane / ABC-type xenobiotic transporter / xenobiotic transport / Paracetamol ADME / Translocases; Catalysing the translocation of other compounds; Linked to the hydrolysis of a nucleoside triphosphate / ABC-type xenobiotic transporter activity / Azathioprine ADME / efflux transmembrane transporter activity / xenobiotic transmembrane transporter activity / transport across blood-brain barrier / ATPase-coupled transmembrane transporter activity / xenobiotic metabolic process / ABC-family proteins mediated transport / transmembrane transport / Golgi lumen / basolateral plasma membrane / endosome membrane / apical plasma membrane / ATP hydrolysis activity / ATP binding / membrane / plasma membrane
Similarity search - Function
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 ...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 5
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.46 Å
AuthorsLiu ZM / Huang Y
Funding support China, 1 items
OrganizationGrant numberCountry
National Science Foundation (NSF, China) China
CitationJournal: Nat Commun / Year: 2024
Title: Inhibition and transport mechanisms of the ABC transporter hMRP5.
Authors: Ying Huang / Chenyang Xue / Ruiqian Bu / Cang Wu / Jiachen Li / Jinqiu Zhang / Jinyu Chen / Zhaoying Shi / Yonglong Chen / Yong Wang / Zhongmin Liu /
Abstract: Human multidrug resistance protein 5 (hMRP5) effluxes anticancer and antivirus drugs, driving multidrug resistance. To uncover the mechanism of hMRP5, we determine six distinct cryo-EM structures, ...Human multidrug resistance protein 5 (hMRP5) effluxes anticancer and antivirus drugs, driving multidrug resistance. To uncover the mechanism of hMRP5, we determine six distinct cryo-EM structures, revealing an autoinhibitory N-terminal peptide that must dissociate to permit subsequent substrate recruitment. Guided by these molecular insights, we design an inhibitory peptide that could block substrate entry into the transport pathway. We also identify a regulatory motif, comprising a positively charged cluster and hydrophobic patches, within the first nucleotide-binding domain that modulates hMRP5 localization by engaging with membranes. By integrating our structural, biochemical, computational, and cell biological findings, we propose a model for hMRP5 conformational cycling and localization. Overall, this work provides mechanistic understanding of hMRP5 function, while informing future selective hMRP5 inhibitor development. More broadly, this study advances our understanding of the structural dynamics and inhibition of ABC transporters.
History
DepositionSep 24, 2023-
Header (metadata) releaseJul 3, 2024-
Map releaseJul 3, 2024-
UpdateJul 3, 2024-
Current statusJul 3, 2024Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_37558.png

Downloads & links

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Map

FileDownload / File: emd_37558.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.)
0.82 Å/pix.
x 300 pix.
= 246. Å		0.82 Å/pix.
x 300 pix.
= 246. Å		0.82 Å/pix.
x 300 pix.
= 246. Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.82 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.1
Minimum - Maximum-2.3532808 - 3.484619
Average (Standard dev.)0.0023742858 (±0.071458705)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 246.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_37558_half_map_1.map
Projections & Slices
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Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_37558_half_map_2.map
Projections & Slices
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Sample components

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Entire : M5PI-bound hMRP5

EntireName: M5PI-bound hMRP5
Components
  • Complex: M5PI-bound hMRP5
    • Protein or peptide: ATP-binding cassette sub-family C member 5
    • Protein or peptide: ATP-binding cassette sub-family C member 5

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Supramolecule #1: M5PI-bound hMRP5

SupramoleculeName: M5PI-bound hMRP5 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: ATP-binding cassette sub-family C member 5

MacromoleculeName: ATP-binding cassette sub-family C member 5 / 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: 150.243906 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: TSKHQHPVDN AGLFSCMTFS WLSSLARVAH KKGELSMEDV WSLSKHESSD VNCRRLERLW QEELNEVGPD AASLRRVVWI FCRTRLILS IVCLMITQLA GFSGPAFMVK HLLEYTQATE SNLQYSLLLV LGLLLTEIVR SWSLALTWAL NYRTGVRLRG A ILTMAFKK ...String:
TSKHQHPVDN AGLFSCMTFS WLSSLARVAH KKGELSMEDV WSLSKHESSD VNCRRLERLW QEELNEVGPD AASLRRVVWI FCRTRLILS IVCLMITQLA GFSGPAFMVK HLLEYTQATE SNLQYSLLLV LGLLLTEIVR SWSLALTWAL NYRTGVRLRG A ILTMAFKK ILKLKNIKEK SLGELINICS NDGQRMFEAA AVGSLLAGGP VVAILGMIYN VIILGPTGFL GSAVFILFYP AM MFASRLT AYFRRKCVAA TDERVQKMNE VLTYIKFIKM YAWVKAFSQS VQKIREEERR ILEKAGYFQS ITVGVAPIVV VIA SVVTFS VHMTLGFDLT AAQAFTVVTV FNSMTFALKV TPFSVKSLSE ASVAVDRFKS LFLMEEVHMI KNKPASPHIK IEMK NATLA WDSSHSSIQN SPKLTPKMKK DKRASRGKKE KVRQLQRTEH QAVLAEQKGH LLLDSDERPS PEEEEGKHIH LGHLR LQRT LHSIDLEIQE GKLVGICGSV GSGKTSLISA ILGQMTLLEG SIAISGTFAY VAQQAWILNA TLRDNILFGK EYDEER YNS VLNSCCLRPD LAILPSSDLT EIGERGANLS GGQRQRISLA RALYSDRSIY ILDDPLSALD AHVGNHIFNS AIRKHLK SK TVLFVTHQLQ YLVDCDEVIF MKEGCITERG THEELMNLNG DYATIFNNLL LGETPPVEIN SKKETSGSQK KSQDKGPK T GSVKKEKAVK PEEGQLVQLE EKGQGSVPWS VYGVYIQAAG GPLAFLVIMA LFMLNVGSTA FSTWWLSYWI KQGSGNTTV TRGNETSVSD SMKDNPHMQY YASIYALSMA VMLILKAIRG VVFVKGTLRA SSRLHDELFR RILRSPMKFF DTTPTGRILN RFSKDMDEV DVRLPFQAEM FIQNVILVFF CVGMIAGVFP WFLVAVGPLV ILFSVLHIVS RVLIRELKRL DNITQSPFLS H ITSSIQGL ATIHAYNKGQ EFLHRYQELL DDNQAPFFLF TCAMRWLAVR LDLISIALIT TTGLMIVLMH GQIPPAYAGL AI SYAVQLT GLFQFTVRLA SETEARFTSV ERINHYIKTL SLEAPARIKN KAPSPDWPQE GEVTFENAEM RYRENLPLVL KKV SFTIKP KEKIGIVGRT GSGKSSLGMA LFRLVELSGG CIKIDGVRIS DIGLADLRSK LSIIPQEPVL FSGTVRSNLD PFNQ YTEDQ IWDALERTHM KECIAQLPLK LESEVMENGD NFSVGERQLL CIARALLRHC KILILDEATA AMDTETDLLI QETIR EAFA DCTMLTIAHR LHTVLGSDRI MVLAQGQVVE FDTPSVLLSN DSSRFYAMFA AAENKVAVKG

UniProtKB: ATP-binding cassette sub-family C member 5

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Macromolecule #2: ATP-binding cassette sub-family C member 5

MacromoleculeName: ATP-binding cassette sub-family C member 5 / type: protein_or_peptide / ID: 2 / 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: 2.519765 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
CQDALETAAR AEGLSLDASM HSQL

UniProtKB: ATP-binding cassette sub-family C member 5

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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: FEI FALCON IV (4k 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: 1.2 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: 3.46 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 944572
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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