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- EMDB-62532: Cryo-EM structure of human ABCC4 (cAMP-bound) -

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Basic information

Entry
Database: EMDB / ID: EMD-62532
TitleCryo-EM structure of human ABCC4 (cAMP-bound)
Map data
Sample
  • Complex: human ABCC4 (cAMP-bound)
    • Protein or peptide: ATP-binding cassette sub-family C member 4
  • Ligand: ADENOSINE-3',5'-CYCLIC-MONOPHOSPHATE
KeywordsABC-type transporter activity / ATP hydrolysis activity / ATPase-coupled transmembrane transporter activity / ATP binding / Transport protein. / TRANSPORT 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 / leukotriene transport / prostaglandin transport / urate transport ...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 / leukotriene transport / prostaglandin transport / urate transport / prostaglandin transmembrane transporter activity / ABC-type glutathione S-conjugate transporter activity / glutathione transmembrane transporter activity / ABC-type glutathione-S-conjugate transporter / urate 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: 2.99 Å
AuthorsLi MH / Wen XP
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: Cell Biosci / Year: 2025
Title: Structural basis of human ABCC4 recognition of cAMP and ligand recognition flexibility.
Authors: Xuepeng Wen / Kaixue Si / Dantong Zhu / Anqi Zhang / Changyou Guo / Minghui Li / Weiming Tian /
Abstract: BACKGROUND: ABCC4 (ATP-binding cassette sub-family C member 4) is a transporter protein that is primarily localized to the plasma membrane, and its efflux activity is associated with the progression ...BACKGROUND: ABCC4 (ATP-binding cassette sub-family C member 4) is a transporter protein that is primarily localized to the plasma membrane, and its efflux activity is associated with the progression of various cancers and the development of drug resistance. Cyclic adenosine monophosphate (cAMP) is an important biomolecule that is considered a transport substrate of ABCC4. However, there is currently no direct structural understanding of how ABCC4 binds cAMP, and the mechanisms by which it recognizes a diverse range of substrate ligands remain poorly understood. Some studies have indicated that, under physiological conditions, cAMP does not significantly stimulate the ATPase activity of ABCC4, making the commonly used ATPase activity assays for ABC proteins unsuitable for studying cAMP.
RESULTS: Here, we successfully resolved the cryo-electron microscopy (cryo-EM) structure of the human ABCC4-cAMP (hABCC4-cAMP) complex, revealing how hABCC4 binds to cAMP and identifying the key ...RESULTS: Here, we successfully resolved the cryo-electron microscopy (cryo-EM) structure of the human ABCC4-cAMP (hABCC4-cAMP) complex, revealing how hABCC4 binds to cAMP and identifying the key residues involved. This structure was compared with two other hABCC4 complex structures we obtained (Methotrexate and Prostaglandin E) and with previously published structures. We discovered some new structural insights into how hABCC4 binds ligands. On the basis of the structural information obtained, we confirmed the feasibility of using 8-[Fluo]-cAMP in a transport assay to detect cAMP translocation and found that some challenges remain to be addressed.
CONCLUSIONS: These results suggest that hABCC4 can bind cAMP and exhibits varying degrees of flexibility when binding with different substrates, including cAMP. These findings expand our ...CONCLUSIONS: These results suggest that hABCC4 can bind cAMP and exhibits varying degrees of flexibility when binding with different substrates, including cAMP. These findings expand our understanding of the structural biology of ABCC4.
History
DepositionNov 28, 2024-
Header (metadata) releaseSep 24, 2025-
Map releaseSep 24, 2025-
UpdateSep 24, 2025-
Current statusSep 24, 2025Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_62532.png

Downloads & links

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Map

FileDownload / File: emd_62532.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

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AxesZ (Sec.)Y (Row.)X (Col.)
1.1 Å/pix.
x 256 pix.
= 281.6 Å		1.1 Å/pix.
x 256 pix.
= 281.6 Å		1.1 Å/pix.
x 256 pix.
= 281.6 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.1 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.24
Minimum - Maximum-3.3470159 - 4.9113846
Average (Standard dev.)-0.0014373207 (±0.08964825)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 281.6 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_62532_half_map_1.map
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Half map: #1

Fileemd_62532_half_map_2.map
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Sample components

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Entire : human ABCC4 (cAMP-bound)

EntireName: human ABCC4 (cAMP-bound)
Components
  • Complex: human ABCC4 (cAMP-bound)
    • Protein or peptide: ATP-binding cassette sub-family C member 4
  • Ligand: ADENOSINE-3',5'-CYCLIC-MONOPHOSPHATE

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Supramolecule #1: human ABCC4 (cAMP-bound)

SupramoleculeName: human ABCC4 (cAMP-bound) / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human) / Location in cell: membrane
Molecular weightTheoretical: 149 kDa/nm

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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: 149.693922 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
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: ADENOSINE-3',5'-CYCLIC-MONOPHOSPHATE

MacromoleculeName: ADENOSINE-3',5'-CYCLIC-MONOPHOSPHATE / type: ligand / ID: 2 / Number of copies: 1 / Formula: CMP
Molecular weightTheoretical: 329.206 Da
Chemical component information

ChemComp-CMP:
ADENOSINE-3',5'-CYCLIC-MONOPHOSPHATE

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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: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.2 µm / Nominal defocus min: 1.2 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: NONE
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.99 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 383488
Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER
FSC plot (resolution estimation)

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