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- EMDB-43543: Cryo-EM structure of human ABC transporter (hABCC1) bound to cGAMP -

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Basic information

Entry
Database: EMDB / ID: EMD-43543
TitleCryo-EM structure of human ABC transporter (hABCC1) bound to cGAMP
Map data
Sample
  • Complex: Homodimer of hABCC1 bound to cGAMP
    • Protein or peptide: Multidrug resistance-associated protein 1
  • Ligand: CHOLESTEROL HEMISUCCINATE
  • Ligand: cGAMP
KeywordscGAMP exporter / ABC transporter / multidrug-resistant protein / homodimer / MEMBRANE PROTEIN
Function / homology
Function and homology information


sphingolipid translocation / cyclic nucleotide transport / Transport of RCbl within the body / ABC-type vitamin B12 transporter activity / carboxylic acid transmembrane transport / carboxylic acid transmembrane transporter activity / cobalamin transport / sphingolipid transporter activity / leukotriene transport / glutathione transmembrane transport ...sphingolipid translocation / cyclic nucleotide transport / Transport of RCbl within the body / ABC-type vitamin B12 transporter activity / carboxylic acid transmembrane transport / carboxylic acid transmembrane transporter activity / cobalamin transport / sphingolipid transporter activity / leukotriene transport / glutathione transmembrane transport / ABC-type glutathione-S-conjugate transporter / ABC-type glutathione S-conjugate transporter activity / glutathione transmembrane transporter activity / leukotriene metabolic process / Synthesis of Leukotrienes (LT) and Eoxins (EX) / ATPase-coupled inorganic anion transmembrane transporter activity / 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 / phospholipid translocation / xenobiotic transport / Heme degradation / efflux transmembrane transporter activity / xenobiotic transmembrane transporter activity / ATPase-coupled transmembrane transporter activity / lateral plasma membrane / 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 / positive regulation of inflammatory response / cellular response to amyloid-beta / 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
Multidrug resistance-associated protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.54 Å
AuthorsShinde O / Li P
Funding support United States, 2 items
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, 2024-
Header (metadata) releaseDec 25, 2024-
Map releaseDec 25, 2024-
UpdateJan 29, 2025-
Current statusJan 29, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_43543.png

Downloads & links

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Map

FileDownload / File: emd_43543.map.gz / Format: CCP4 / Size: 144.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 336 pix.
= 279.552 Å		0.83 Å/pix.
x 336 pix.
= 279.552 Å		0.83 Å/pix.
x 336 pix.
= 279.552 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.832 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.06
Minimum - Maximum-0.487687 - 0.7046101
Average (Standard dev.)0.0013126883 (±0.017215112)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions336336336
Spacing336336336
CellA=B=C: 279.552 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_43543_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_43543_half_map_2.map
Projections & Slices
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Histogram

Histogram (log scale)

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Sample components

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Entire : Homodimer of hABCC1 bound to cGAMP

EntireName: Homodimer of hABCC1 bound to cGAMP
Components
  • Complex: Homodimer of hABCC1 bound to cGAMP
    • Protein or peptide: Multidrug resistance-associated protein 1
  • Ligand: CHOLESTEROL HEMISUCCINATE
  • Ligand: cGAMP

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Supramolecule #1: Homodimer of hABCC1 bound to cGAMP

SupramoleculeName: Homodimer of hABCC1 bound to cGAMP / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 199 KDa

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Macromolecule #1: Multidrug resistance-associated protein 1

MacromoleculeName: Multidrug resistance-associated protein 1 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: ABC-type xenobiotic transporter
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 171.762953 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MALRGFCSAD GSDPLWDWNV TWNTSNPDFT KCFQNTVLVW VPCFYLWACF PFYFLYLSRH DRGYIQMTPL NKTKTALGFL LWIVCWADL FYSFWERSRG IFLAPVFLVS PTLLGITMLL ATFLIQLERR KGVQSSGIML TFWLVALVCA LAILRSKIMT A LKEDAQVD ...String:
MALRGFCSAD GSDPLWDWNV TWNTSNPDFT KCFQNTVLVW VPCFYLWACF PFYFLYLSRH DRGYIQMTPL NKTKTALGFL LWIVCWADL FYSFWERSRG IFLAPVFLVS PTLLGITMLL ATFLIQLERR KGVQSSGIML TFWLVALVCA LAILRSKIMT A LKEDAQVD LFRDITFYVY FSLLLIQLVL SCFSDRSPLF SETIHDPNPC PESSASFLSR ITFWWITGLI VRGYRQPLEG SD LWSLNKE DTSEQVVPVL VKNWKKECAK TRKQPVKVVY SSKDPAQPKE SSKVDANEEV EALIVKSPQK EWNPSLFKVL YKT FGPYFL MSFFFKAIHD LMMFSGPQIL KLLIKFVNDT KAPDWQGYFY TVLLFVTACL QTLVLHQYFH ICFVSGMRIK TAVI GAVYR KALVITNSAR KSSTVGEIVN LMSVDAQRFM DLATYINMIW SAPLQVILAL YLLWLNLGPS VLAGVAVMVL MVPVN AVMA MKTKTYQVAH MKSKDNRIKL MNEILNGIKV LKLYAWELAF KDKVLAIRQE ELKVLKKSAY LSAVGTFTWV CTPFLV ALC TFAVYVTIDE NNILDAQTAF VSLALFNILR FPLNILPMVI SSIVQASVSL KRLRIFLSHE ELEPDSIERR PVKDGGG TN SITVRNATFT WARSDPPTLN GITFSIPEGA LVAVVGQVGC GKSSLLSALL AEMDKVEGHV AIKGSVAYVP QQAWIQND S LRENILFGCQ LEEPYYRSVI QACALLPDLE ILPSGDRTEI GEKGVNLSGG QKQRVSLARA VYSNADIYLF DDPLSAVDA HVGKHIFENV IGPKGMLKNK TRILVTHSMS YLPQVDVIIV MSGGKISEMG SYQELLARDG AFAEFLRTYA STEQEQDAEE NGVTGVSGP GKEAKQMENG MLVTDSAGKQ LQRQLSSSSS YSGDISRHHN STAELQKAEA KKEETWKLME ADKAQTGQVK L SVYWDYMK AIGLFISFLS IFLFMCNHVS ALASNYWLSL WTDDPIVNGT QEHTKVRLSV YGALGISQGI AVFGYSMAVS IG GILASRC LHVDLLHSIL RSPMSFFERT PSGNLVNRFS KELDTVDSMI PEVIKMFMGS LFNVIGACIV ILLATPIAAI IIP PLGLIY FFVQRFYVAS SRQLKRLESV SRSPVYSHFN ETLLGVSVIR AFEEQERFIH QSDLKVDENQ KAYYPSIVAN RWLA VRLEC VGNCIVLFAA LFAVISRHSL SAGLVGLSVS YSLQVTTYLN WLVRMSSEME TNIVAVERLK EYSETEKEAP WQIQE TAPP SSWPQVGRVE FRNYCLRYRE DLDFVLRHIN VTINGGEKVG IVGRTGAGKS SLTLGLFRIN ESAEGEIIID GINIAK IGL HDLRFKITII PQDPVLFSGS LRMNLDPFSQ YSDEEVWTSL ELAHLKDFVS ALPDKLDHEC AEGGENLSVG QRQLVCL AR ALLRKTKILV LDEATAAVDL ETDDLIQSTI RTQFEDCTVL TIAHRLNTIM DYTRVIVLDK GEIQEYGAPS DLLQQRGL F YSMAKDAGLV

UniProtKB: Multidrug resistance-associated protein 1

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Macromolecule #2: CHOLESTEROL HEMISUCCINATE

MacromoleculeName: CHOLESTEROL HEMISUCCINATE / type: ligand / ID: 2 / Number of copies: 2 / Formula: Y01
Molecular weightTheoretical: 486.726 Da
Chemical component information

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

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Macromolecule #3: cGAMP

MacromoleculeName: cGAMP / type: ligand / ID: 3 / Number of copies: 1 / Formula: 1SY
Molecular weightTheoretical: 674.411 Da
Chemical component information

ChemComp-1SY:
cGAMP

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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

Concentration2.0 mg/mL
BufferpH: 7.5
Component:
ConcentrationFormulaName
20.0 mMTris-HClTris-HCl
150.0 mMNaClSodium chloride
2.0 mMMgCl2Magnesium chloride
0.1 mMC20H24N10O13P2Cyclic guanosine monophosphate adenosine monophosphate
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 30 sec. / Pretreatment - Atmosphere: AIR
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: SPOT SCAN / Imaging mode: OTHER / Cs: 2.7 mm / Nominal defocus max: 2.2 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 1427521
Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.54 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 80454
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
FSC plot (resolution estimation)

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