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- PDB-8vux: Cryo-EM structure of human ABC transporter (hABCC1) bound to cGAMP -

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Basic information

Entry
Database: PDB / ID: 8vux
TitleCryo-EM structure of human ABC transporter (hABCC1) bound to cGAMP
ComponentsMultidrug resistance-associated protein 1
KeywordsMEMBRANE PROTEIN / cGAMP exporter / ABC transporter / multidrug-resistant protein / homodimer
Function / homology
Function and homology information


ATPase-coupled carboxylic acid transmembrane transporter activity / pigment accumulation / antigen processing and presentation of lipid antigen via MHC class Ib / sphingolipid translocation / intracellular nitrogen homeostasis / granuloma formation / ABC-type vitamin B12 transporter activity / Transport of RCbl within the body / cyclic nucleotide transport / NK T cell activation ...ATPase-coupled carboxylic acid transmembrane transporter activity / pigment accumulation / antigen processing and presentation of lipid antigen via MHC class Ib / sphingolipid translocation / intracellular nitrogen homeostasis / granuloma formation / ABC-type vitamin B12 transporter activity / Transport of RCbl within the body / cyclic nucleotide transport / NK T cell activation / bilirubin transmembrane transporter activity / neural tissue regeneration / amygdala development / cobalamin transport / sphingolipid intramembrane carrier activity / lymphocyte migration / glutathione transmembrane transport / leukotriene transport / endothelium development / carboxylic acid transmembrane transport / ABC-type glutathione-S-conjugate transporter / leukotriene metabolic process / glucocorticoid metabolic process / glutathione transmembrane transporter activity / ABC-type glutathione S-conjugate transporter activity / Synthesis of Leukotrienes (LT) and Eoxins (EX) / carboxylic acid transmembrane transporter activity / : / sphingolipid biosynthetic process / Sphingolipid de novo biosynthesis / macrophage activation / tissue homeostasis / heme catabolic process / xenobiotic transport across blood-brain barrier / response to fluid shear stress / endothelial cell apoptotic process / ATPase-coupled lipid transmembrane transporter activity / Paracetamol ADME / leukotriene biosynthetic process / export across plasma membrane / NFE2L2 regulating MDR associated enzymes / inflammatory response to antigenic stimulus / transepithelial transport / ABC-type xenobiotic transporter / hydrogen peroxide biosynthetic process / protein localization to cell surface / superoxide anion generation / Heme degradation / ABC-type xenobiotic transporter activity / phospholipid translocation / exploration behavior / amyloid-beta clearance / ATPase-coupled transmembrane transporter activity / efflux transmembrane transporter activity / lateral plasma membrane / xenobiotic transmembrane transporter activity / amyloid-beta metabolic process / ABC-type transporter activity / xenobiotic transport / transport across blood-brain barrier / xenobiotic metabolic process / neurogenesis / cell redox homeostasis / response to glucocorticoid / establishment of localization in cell / basal plasma membrane / blood vessel diameter maintenance / cell chemotaxis / hippocampus development / glutathione metabolic process / regulation of membrane potential / Cytoprotection by HMOX1 / ABC-family proteins mediated transport / cellular response to type II interferon / transmembrane transport / response to toxic substance / multicellular organism growth / cellular response to amyloid-beta / memory / positive regulation of inflammatory response / cellular response to oxidative stress / gene expression / basolateral plasma membrane / apical plasma membrane / defense response to Gram-positive bacterium / 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
cGAMP / CHOLESTEROL HEMISUCCINATE / Multidrug resistance-associated protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.54 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 30, 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 ..._citation.journal_volume / _citation.page_first / _citation.page_last / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)345,1745
Polymers343,5262
Non-polymers1,6483
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
#3: Chemical ChemComp-1SY / cGAMP / 2',3' cGAMP / c-GMP-AMP / c[G(2',5')pA(3',5')p]


Mass: 674.411 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H24N10O13P2 / 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: Homodimer of hABCC1 bound to cGAMP / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.199 MDa / 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
40.1 mMCyclic guanosine monophosphate adenosine monophosphateC20H24N10O13P21
SpecimenConc.: 2 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 R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277.15 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 / Cs: 2.7 mm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameCategory
1cryoSPARCparticle selection
2EPUimage acquisition
4cryoSPARCCTF correction
10cryoSPARCinitial Euler assignment
11cryoSPARCfinal Euler assignment
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 1427521
3D reconstructionResolution: 3.54 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 80454 / Symmetry type: POINT

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