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- PDB-8vt4: Cryo-EM structure of human ABC transporter ABCC1 -

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Basic information

Entry
Database: PDB / ID: 8vt4
TitleCryo-EM structure of human ABC transporter ABCC1
ComponentsMultidrug resistance-associated protein 1
KeywordsMEMBRANE PROTEIN / Organic anion exporter / ATPase-dependent export / homodimer / multidrug-resistant protein
Function / homology
Function and homology information


sphingolipid translocation / Transport of RCbl within the body / ABC-type vitamin B12 transporter activity / cyclic nucleotide transport / carboxylic acid transmembrane transport / carboxylic acid transmembrane transporter activity / cobalamin transport / sphingolipid transporter activity / glutathione transmembrane transport / leukotriene transport ...sphingolipid translocation / Transport of RCbl within the body / ABC-type vitamin B12 transporter activity / cyclic nucleotide transport / carboxylic acid transmembrane transport / carboxylic acid transmembrane transporter activity / cobalamin transport / sphingolipid transporter activity / glutathione transmembrane transport / leukotriene transport / leukotriene metabolic process / ABC-type glutathione S-conjugate transporter activity / glutathione transmembrane transporter activity / ABC-type glutathione-S-conjugate transporter / Synthesis of Leukotrienes (LT) and Eoxins (EX) / sphingolipid biosynthetic process / : / Sphingolipid de novo biosynthesis / heme catabolic process / xenobiotic transport across blood-brain barrier / transepithelial transport / ATPase-coupled lipid transmembrane transporter activity / export across plasma membrane / Paracetamol ADME / NFE2L2 regulating MDR associated enzymes / ABC-type xenobiotic transporter / ABC-type xenobiotic transporter activity / Heme degradation / phospholipid translocation / xenobiotic transport / efflux transmembrane transporter activity / lateral plasma membrane / xenobiotic transmembrane transporter activity / ATPase-coupled transmembrane transporter activity / ABC-type transporter activity / transport across blood-brain barrier / xenobiotic metabolic process / basal plasma membrane / cell chemotaxis / Cytoprotection by HMOX1 / ABC-family proteins mediated transport / transmembrane transport / cellular response to amyloid-beta / positive regulation of inflammatory response / cellular response to oxidative stress / basolateral plasma membrane / apical plasma membrane / response to xenobiotic stimulus / ATP hydrolysis activity / extracellular exosome / ATP binding / membrane / plasma membrane
Similarity search - Function
Multi drug resistance-associated protein / : / ABC transporter TMD0 domain / : / 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. ...Multi drug resistance-associated protein / : / ABC transporter TMD0 domain / : / 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
CHOLESTEROL HEMISUCCINATE / Multidrug resistance-associated protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.79 Å
AuthorsShinde, O. / Li, P.
Funding support United States, 2items
OrganizationGrant numberCountry
Welch FoundationA-2107 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)AI145287 United States
CitationJournal: Immunity / Year: 2025
Title: Structures of ATP-binding cassette transporter ABCC1 reveal the molecular basis of cyclic dinucleotide cGAMP export.
Authors: Omkar Shinde / Joshua A Boyer / Stephanie Cambier / Jordyn J VanPortfliet / Xuewu Sui / Gaya P Yadav / Elizabeth G Viverette / Mario J Borgnia / A Phillip West / Qi Zhang / Daniel B Stetson / Pingwei Li /
Abstract: Cyclic nucleotide GMP-AMP (cGAMP) plays a critical role in mediating the innate immune response through the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. Recent ...Cyclic nucleotide GMP-AMP (cGAMP) plays a critical role in mediating the innate immune response through the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. Recent studies showed that ATP-binding cassette subfamily C member 1 (ABCC1) is a cGAMP exporter. The exported cGAMP can be imported into uninfected cells to stimulate a STING-mediated innate immune response. However, the molecular basis of cGAMP export mediated by ABCC1 remains unclear. Here, we report the cryoelectron microscopy (cryo-EM) structures of human ABCC1 in a ligand-free state and a cGAMP-bound state. These structures reveal that ABCC1 forms a homodimer via its N-terminal transmembrane domain. The ligand-bound structure shows that cGAMP is recognized by a positively charged pocket. Mutagenesis and functional studies confirmed the roles of the ligand-binding pocket in cGAMP recognition and export. This study provides insights into the structure and function of ABCC1 as a cGAMP exporter and lays a foundation for future research targeting ABCC1 in infection and anti-cancer immunity.
History
DepositionJan 25, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 25, 2024Provider: repository / Type: Initial release
Revision 1.1Jan 22, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update
Revision 1.2Jan 29, 2025Group: Data collection / Database references / Category: citation / em_admin
Item: _citation.journal_volume / _citation.page_first / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Multidrug resistance-associated protein 1
B: Multidrug resistance-associated protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)344,4994
Polymers343,5262
Non-polymers9732
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein Multidrug resistance-associated protein 1 / ATP-binding cassette sub-family C member 1 / Glutathione-S-conjugate-translocating ATPase ABCC1 / ...ATP-binding cassette sub-family C member 1 / Glutathione-S-conjugate-translocating ATPase ABCC1 / Leukotriene C(4) transporter / LTC4 transporter


Mass: 171762.953 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ABCC1, MRP, MRP1 / Production host: Homo sapiens (human)
References: UniProt: P33527, ABC-type xenobiotic transporter, ABC-type glutathione-S-conjugate transporter
#2: Chemical ChemComp-Y01 / CHOLESTEROL HEMISUCCINATE


Mass: 486.726 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C31H50O4 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationY

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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 ATP Binding Cassette Subfamily C Member 1 (hABCC1) in complex with cholesterol hemisuccinate
Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 200 kDa/nm / Experimental value: YES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
Buffer component
IDConc.NameFormulaBuffer-ID
120 mMTris-HClTris-HCl1
2150 mMSodium ChlorideNaCl1
32 mMMagnesium chlorideMgCl21
SpecimenConc.: 2.46 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R2/1
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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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: SPOT SCAN
Electron lensMode: OTHER / Nominal defocus max: 2200 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 48 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 35

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Processing

EM software
IDNameCategory
2EPUimage acquisition
4cryoSPARCCTF correction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.79 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 220485 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 82.84 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.002816448
ELECTRON MICROSCOPYf_angle_d0.569322382
ELECTRON MICROSCOPYf_chiral_restr0.04052608
ELECTRON MICROSCOPYf_plane_restr0.00442754
ELECTRON MICROSCOPYf_dihedral_angle_d4.52132198

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