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- PDB-9krl: Cryo-EM structure of human ABCC4 (cAMP-bound) -

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Basic information

Entry
Database: PDB / ID: 9krl
TitleCryo-EM structure of human ABCC4 (cAMP-bound)
ComponentsATP-binding cassette sub-family C member 4
KeywordsTRANSPORT PROTEIN / ABC-type transporter activity / ATP hydrolysis activity / ATPase-coupled transmembrane transporter activity / ATP binding / 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 / ABC-type glutathione S-conjugate 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 / leukotriene transport / prostaglandin transport / ABC-type glutathione S-conjugate transporter activity / glutathione transmembrane transporter activity / ABC-type glutathione-S-conjugate transporter / urate transport / prostaglandin transmembrane transporter activity / 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
ADENOSINE-3',5'-CYCLIC-MONOPHOSPHATE / ATP-binding cassette sub-family C member 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.99 Å
AuthorsLi, M.H. / Wen, X.P.
Funding support1items
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, 2024Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Sep 24, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: ATP-binding cassette sub-family C member 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)150,0232
Polymers149,6941
Non-polymers3291
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein ATP-binding cassette sub-family C member 4 / MRP/cMOAT-related ABC transporter / Multi-specific organic anion transporter B / MOAT-B / Multidrug ...MRP/cMOAT-related ABC transporter / Multi-specific organic anion transporter B / MOAT-B / Multidrug resistance-associated protein 4


Mass: 149693.922 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ABCC4, MOATB, MRP4 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: O15439, Translocases; Catalysing the translocation of other compounds; Linked to the hydrolysis of a nucleoside triphosphate, ABC-type xenobiotic transporter, ABC-type ...References: UniProt: O15439, Translocases; Catalysing the translocation of other compounds; Linked to the hydrolysis of a nucleoside triphosphate, ABC-type xenobiotic transporter, ABC-type glutathione-S-conjugate transporter
#2: Chemical ChemComp-CMP / ADENOSINE-3',5'-CYCLIC-MONOPHOSPHATE / CYCLIC AMP / CAMP


Mass: 329.206 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H12N5O6P / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: human ABCC4 (cAMP-bound) / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 149 kDa/nm / Experimental value: NO
Source (natural)Organism: Homo sapiens (human) / Cellular location: membrane
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2200 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.16_3549 / Category: model refinement
CTF correctionType: NONE
3D reconstructionResolution: 2.99 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 383488 / Symmetry type: POINT
RefinementStereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00315460
ELECTRON MICROSCOPYf_angle_d0.52928004
ELECTRON MICROSCOPYf_dihedral_angle_d7.8986207
ELECTRON MICROSCOPYf_chiral_restr0.0381222
ELECTRON MICROSCOPYf_plane_restr0.0022189

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