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- EMDB-38533: Cryo-EM structure of human ABCC4 with ANP bound in NBD1 -

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Basic information

Entry
Database: EMDB / ID: EMD-38533
TitleCryo-EM structure of human ABCC4 with ANP bound in NBD1
Map dataC4AMP
Sample
  • Organelle or cellular component: human ABCC4 in complex with ANP-bound in NBD1
    • Protein or peptide: ATP-binding cassette sub-family C member 4
  • Ligand: PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER
  • Ligand: 2-[2-[(1~{S},2~{S},4~{S},5'~{R},6~{R},7~{S},8~{R},9~{S},12~{S},13~{R},16~{S})-5',7,9,13-tetramethylspiro[5-oxapentacyclo[10.8.0.0^{2,9}.0^{4,8}.0^{13,18}]icos-18-ene-6,2'-oxane]-16-yl]oxyethyl]propane-1,3-diol
  • Ligand: PALMITIC ACID
  • Ligand: MAGNESIUM ION
KeywordsABC transporter MRP / TRANSPORT PROTEIN
Function / homology
Function and homology information


guanine nucleotide transmembrane transporter activity / 15-hydroxyprostaglandin dehydrogenase (NAD+) activity / purine nucleotide transmembrane transporter activity / cAMP transport / ABC-type bile acid transporter activity / platelet dense granule membrane / leukotriene transport / urate transport / platelet degranulation / prostaglandin transport ...guanine nucleotide transmembrane transporter activity / 15-hydroxyprostaglandin dehydrogenase (NAD+) activity / purine nucleotide transmembrane transporter activity / cAMP transport / ABC-type bile acid transporter activity / platelet dense granule membrane / leukotriene transport / urate transport / platelet degranulation / prostaglandin transport / glutathione transmembrane transporter activity / ABC-type glutathione-S-conjugate transporter / prostaglandin transmembrane transporter activity / ABC-type glutathione S-conjugate transporter activity / urate transmembrane transporter activity / ATPase-coupled inorganic anion transmembrane transporter activity / external side of apical plasma membrane / xenobiotic transmembrane transport / export across plasma membrane / ABC-type xenobiotic transporter / prostaglandin secretion / Paracetamol ADME / Translocases; Catalysing the translocation of other compounds; Linked to the hydrolysis of a nucleoside triphosphate / ABC-type xenobiotic transporter activity / Azathioprine ADME / bile acid and bile salt transport / efflux transmembrane transporter activity / xenobiotic transmembrane transporter activity / ATPase-coupled transmembrane transporter activity / transport across blood-brain barrier / cilium assembly / ABC-type transporter activity / xenobiotic metabolic process / ABC-family proteins mediated transport / transmembrane transport / Platelet degranulation / basolateral plasma membrane / apical plasma membrane / 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: 3.02 Å
AuthorsZhang PF / Liu Z
Funding support China, 1 items
OrganizationGrant numberCountry
Not funded China
CitationJournal: FEBS Lett / Year: 2024
Title: The ATP-bound inward-open conformation of ABCC4 reveals asymmetric ATP binding for substrate transport.
Authors: Yue Zhu / Xiaoke Xing / Fuxing Wang / Luojun Chen / Chunhui Zhong / Xiting Lu / Zhanwang Yu / Yongbo Yang / Yi Yao / Qibin Song / Suxia Han / Zheng Liu / Pingfeng Zhang /
Abstract: The multidrug resistance-associated protein (MRP) ABCC4 facilitates substrate transport across the cytoplasmic membrane, crucial for normal physiology and mediating multidrug resistance in tumor ...The multidrug resistance-associated protein (MRP) ABCC4 facilitates substrate transport across the cytoplasmic membrane, crucial for normal physiology and mediating multidrug resistance in tumor cells. Despite intensive studies on MRPs, ABCC4's transport mechanism remains incompletely understood. In this study, we unveiled an inward-open conformation with an ATP bound to degenerate NBD1. Additionally, we captured the structure with both ATP and substrate co-bound in the inward-open state. Our findings uncover the asymmetric ATP binding in ABCC4 and provide insights into substrate binding and transport mechanisms. ATP binding to NBD1 is parallel to substrate binding to ABCC4, and is a prerequisite for ATP-bound NBD2-induced global conformational changes. Our findings shed new light on targeting ABCC4 in combination with anticancer therapy.
History
DepositionJan 1, 2024-
Header (metadata) releaseJul 17, 2024-
Map releaseJul 17, 2024-
UpdateSep 4, 2024-
Current statusSep 4, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_38533.png

Downloads & links

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Map

FileDownload / File: emd_38533.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationC4AMP
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 256 pix.
= 212.48 Å		0.83 Å/pix.
x 256 pix.
= 212.48 Å		0.83 Å/pix.
x 256 pix.
= 212.48 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.83 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0505
Minimum - Maximum-0.15994434 - 0.27857876
Average (Standard dev.)0.000901576 (±0.013085921)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 212.48 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: C4AMP half map B

Fileemd_38533_half_map_1.map
AnnotationC4AMP half map B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: C4AMP half map A

Fileemd_38533_half_map_2.map
AnnotationC4AMP half map A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : human ABCC4 in complex with ANP-bound in NBD1

EntireName: human ABCC4 in complex with ANP-bound in NBD1
Components
  • Organelle or cellular component: human ABCC4 in complex with ANP-bound in NBD1
    • Protein or peptide: ATP-binding cassette sub-family C member 4
  • Ligand: PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER
  • Ligand: 2-[2-[(1~{S},2~{S},4~{S},5'~{R},6~{R},7~{S},8~{R},9~{S},12~{S},13~{R},16~{S})-5',7,9,13-tetramethylspiro[5-oxapentacyclo[10.8.0.0^{2,9}.0^{4,8}.0^{13,18}]icos-18-ene-6,2'-oxane]-16-yl]oxyethyl]propane-1,3-diol
  • Ligand: PALMITIC ACID
  • Ligand: MAGNESIUM ION

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Supramolecule #1: human ABCC4 in complex with ANP-bound in NBD1

SupramoleculeName: human ABCC4 in complex with ANP-bound in NBD1 / type: organelle_or_cellular_component / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 149.5 KDa

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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: ABC-type xenobiotic transporter
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 149.693922 KDa
Recombinant expressionOrganism: Mammalian expression vector Flag-MCS-pcDNA3.1 (others)
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 L

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

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Macromolecule #2: PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER

MacromoleculeName: PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER / type: ligand / ID: 2 / Number of copies: 1 / Formula: ANP
Molecular weightTheoretical: 506.196 Da
Chemical component information

ChemComp-ANP:
PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER / AMP-PNP, energy-carrying molecule analogue*YM

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Macromolecule #3: 2-[2-[(1~{S},2~{S},4~{S},5'~{R},6~{R},7~{S},8~{R},9~{S},12~{S},13...

MacromoleculeName: 2-[2-[(1~{S},2~{S},4~{S},5'~{R},6~{R},7~{S},8~{R},9~{S},12~{S},13~{R},16~{S})-5',7,9,13-tetramethylspiro[5-oxapentacyclo[10.8.0.0^{2,9}.0^{4,8}.0^{13,18}]icos-18-ene-6,2'-oxane]-16-yl]oxyethyl]propane-1,3-diol
type: ligand / ID: 3 / Number of copies: 8 / Formula: DU0
Molecular weightTheoretical: 516.752 Da
Chemical component information

ChemComp-DU0:
2-[2-[(1~{S},2~{S},4~{S},5'~{R},6~{R},7~{S},8~{R},9~{S},12~{S},13~{R},16~{S})-5',7,9,13-tetramethylspiro[5-oxapentacyclo[10.8.0.0^{2,9}.0^{4,8}.0^{13,18}]icos-18-ene-6,2'-oxane]-16-yl]oxyethyl]propane-1,3-diol

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Macromolecule #4: PALMITIC ACID

MacromoleculeName: PALMITIC ACID / type: ligand / ID: 4 / Number of copies: 1 / Formula: PLM
Molecular weightTheoretical: 256.424 Da
Chemical component information

ChemComp-PLM:
PALMITIC ACID

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Macromolecule #5: MAGNESIUM ION

MacromoleculeName: MAGNESIUM ION / type: ligand / ID: 5 / Number of copies: 1 / Formula: MG
Molecular weightTheoretical: 24.305 Da

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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

Concentration10 mg/mL
BufferpH: 7.5 / Component - Concentration: 25.0 mM / Component - Name: Hepes
Details: 50 mM HEPES pH 7.5, 150 mM NaCl, 2 mM DTT, 2 mM MgCl2, 0.005% (w/v) GDN and 0.0005% CHS
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV
Details: After incubation on the grids at 277K under 100% humidity for 10 s, the grids were bloted for 3.0 s and then plunged frozen into liquid ethane cooled by liquid nitrogen using a Vitrobot..
DetailsThe human ABCC4 protein was purified in 0.005% (w/v) GDN and 0.0005% CHS, the peak protein fraction from gel filtration column were concentrated to about 10 mg/ml.

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 55.0 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: 1.1 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 4482384
Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.02 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 1223229
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: PROJECTION MATCHING

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Atomic model buiding 1

RefinementSpace: REAL
Output model

PDB-8xol:
Cryo-EM structure of human ABCC4 with ANP bound in NBD1

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