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- EMDB-44332: Cryo-EM structure of human ADAR1 in complex with dsRNA derived fr... -

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Basic information

Entry
Database: EMDB / ID: EMD-44332
TitleCryo-EM structure of human ADAR1 in complex with dsRNA derived from HT2C gene
Map data
Sample
  • Complex: human ADAR1 in complex with dsRNA derived from HT2C gene
    • Protein or peptide: Maltodextrin-binding protein,Double-stranded RNA-specific adenosine deaminase
    • RNA: RNA (66-MER)
  • Ligand: INOSITOL HEXAKISPHOSPHATE
  • Ligand: ZINC ION
KeywordsADAR1 complex with dsRNA / HYDROLASE-RNA complex
Function / homology
Function and homology information


somatic diversification of immune receptors via somatic mutation / negative regulation of post-transcriptional gene silencing by regulatory ncRNA / C6 deamination of adenosine / Formation of editosomes by ADAR proteins / supraspliceosomal complex / double-stranded RNA adenine deaminase / tRNA-specific adenosine deaminase activity / adenosine to inosine editing / negative regulation of protein kinase activity by regulation of protein phosphorylation / double-stranded RNA adenosine deaminase activity ...somatic diversification of immune receptors via somatic mutation / negative regulation of post-transcriptional gene silencing by regulatory ncRNA / C6 deamination of adenosine / Formation of editosomes by ADAR proteins / supraspliceosomal complex / double-stranded RNA adenine deaminase / tRNA-specific adenosine deaminase activity / adenosine to inosine editing / negative regulation of protein kinase activity by regulation of protein phosphorylation / double-stranded RNA adenosine deaminase activity / base conversion or substitution editing / response to interferon-alpha / hematopoietic stem cell homeostasis / adenosine deaminase activity / RISC complex assembly / pre-miRNA processing / negative regulation of hepatocyte apoptotic process / definitive hemopoiesis / negative regulation of type I interferon-mediated signaling pathway / hepatocyte apoptotic process / carbohydrate transmembrane transporter activity / maltose binding / maltose transport / maltodextrin transmembrane transport / positive regulation of viral genome replication / RNA processing / hematopoietic progenitor cell differentiation / ATP-binding cassette (ABC) transporter complex, substrate-binding subunit-containing / protein export from nucleus / erythrocyte differentiation / PKR-mediated signaling / response to virus / cellular response to virus / mRNA processing / protein import into nucleus / osteoblast differentiation / Interferon alpha/beta signaling / double-stranded RNA binding / outer membrane-bounded periplasmic space / defense response to virus / innate immune response / nucleolus / mitochondrion / DNA binding / RNA binding / nucleoplasm / metal ion binding / nucleus / membrane / cytosol / cytoplasm
Similarity search - Function
ADAR1, first double-stranded RNA binding domain / ADAR1, third double-stranded RNA binding domain / Z-DNA-binding domain in adenosine deaminases. / Z-binding domain / Adenosine deaminase z-alpha domain / Z-binding domain profile. / Adenosine deaminase/editase / Adenosine-deaminase (editase) domain / Adenosine to inosine editase domain profile. / tRNA-specific and double-stranded RNA adenosine deaminase (RNA-specific editase) ...ADAR1, first double-stranded RNA binding domain / ADAR1, third double-stranded RNA binding domain / Z-DNA-binding domain in adenosine deaminases. / Z-binding domain / Adenosine deaminase z-alpha domain / Z-binding domain profile. / Adenosine deaminase/editase / Adenosine-deaminase (editase) domain / Adenosine to inosine editase domain profile. / tRNA-specific and double-stranded RNA adenosine deaminase (RNA-specific editase) / Double-stranded RNA binding motif / Double-stranded RNA binding motif / Double stranded RNA-binding domain (dsRBD) profile. / Double-stranded RNA-binding domain / Maltose/Cyclodextrin ABC transporter, substrate-binding protein / Solute-binding family 1, conserved site / Bacterial extracellular solute-binding proteins, family 1 signature. / Bacterial extracellular solute-binding protein / Bacterial extracellular solute-binding protein / Winged helix DNA-binding domain superfamily / Winged helix-like DNA-binding domain superfamily
Similarity search - Domain/homology
Maltodextrin-binding protein / Double-stranded RNA-specific adenosine deaminase
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsDeng X / Gao Y
Funding support United States, 1 items
OrganizationGrant numberCountry
Cancer Prevention and Research Institute of Texas (CPRIT)RP190602 United States
CitationJournal: Mol Cell / Year: 2025
Title: Biochemical profiling and structural basis of ADAR1-mediated RNA editing.
Authors: Xiangyu Deng / Lina Sun / Min Zhang / Rashmi Basavaraj / Jin Wang / Yi-Lan Weng / Yang Gao /
Abstract: ADAR1 regulates RNA-induced immune responses by converting adenosine to inosine in double-stranded RNA. Mutations in ADAR1 are associated with human autoimmune disease, and targeting ADAR1 has been ...ADAR1 regulates RNA-induced immune responses by converting adenosine to inosine in double-stranded RNA. Mutations in ADAR1 are associated with human autoimmune disease, and targeting ADAR1 has been proposed for cancer immunotherapy. However, the molecular mechanisms underlying ADAR1-mediated editing remain unclear. Here, we provide detailed biochemical and structural characterizations of human ADAR1. Our biochemical profiling reveals that ADAR1 editing is both sequence and RNA-duplex-length dependent but can well tolerate mismatches near the editing site. High-resolution ADAR1-RNA complex structures, combined with mutagenesis, elucidate RNA binding, substrate selection, dimerization, and the essential role of RNA-binding domain 3. The ADAR1 structures also help explain the potential defects of disease-associated mutations, where biochemical and RNA sequencing analysis further indicate some of the mutations preferentially impact the editing of RNAs with short duplexes. These findings unveil the molecular basis of ADAR1 editing and provide insights into its immune-regulatory functions and therapeutic potential.
History
DepositionMar 28, 2024-
Header (metadata) releaseMar 26, 2025-
Map releaseMar 26, 2025-
UpdateApr 16, 2025-
Current statusApr 16, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_44332.png

Downloads & links

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Map

FileDownload / File: emd_44332.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.95 Å/pix.
x 320 pix.
= 302.72 Å		0.95 Å/pix.
x 320 pix.
= 302.72 Å		0.95 Å/pix.
x 320 pix.
= 302.72 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.946 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.538
Minimum - Maximum-7.2597256 - 10.978180999999999
Average (Standard dev.)0.00097266363 (±0.12964189)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 302.72 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_44332_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_44332_half_map_2.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : human ADAR1 in complex with dsRNA derived from HT2C gene

EntireName: human ADAR1 in complex with dsRNA derived from HT2C gene
Components
  • Complex: human ADAR1 in complex with dsRNA derived from HT2C gene
    • Protein or peptide: Maltodextrin-binding protein,Double-stranded RNA-specific adenosine deaminase
    • RNA: RNA (66-MER)
  • Ligand: INOSITOL HEXAKISPHOSPHATE
  • Ligand: ZINC ION

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Supramolecule #1: human ADAR1 in complex with dsRNA derived from HT2C gene

SupramoleculeName: human ADAR1 in complex with dsRNA derived from HT2C gene
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Maltodextrin-binding protein,Double-stranded RNA-specific adenosi...

MacromoleculeName: Maltodextrin-binding protein,Double-stranded RNA-specific adenosine deaminase
type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: double-stranded RNA adenine deaminase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 165.251234 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MKIEEGKLVI WINGDKGYNG LAEVGKKFEK DTGIKVTVEH PDKLEEKFPQ VAATGDGPDI IFWAHDRFGG YAQSGLLAEI TPDKAFQDK LYPFTWDAVR YNGKLIAYPI AVEALSLIYN KDLLPNPPKT WEEIPALDKE LKAKGKSALM FNLQEPYFTW P LIAADGGY ...String:
MKIEEGKLVI WINGDKGYNG LAEVGKKFEK DTGIKVTVEH PDKLEEKFPQ VAATGDGPDI IFWAHDRFGG YAQSGLLAEI TPDKAFQDK LYPFTWDAVR YNGKLIAYPI AVEALSLIYN KDLLPNPPKT WEEIPALDKE LKAKGKSALM FNLQEPYFTW P LIAADGGY AFKYENGKYD IKDVGVDNAG AKAGLTFLVD LIKNKHMNAD TDYSIAEAAF NKGETAMTIN GPWAWSNIDT SK VNYGVTV LPTFKGQPSK PFVGVLSAGI NAASPNKELA KEFLENYLLT DEGLEAVNKD KPLGAVALKS YEEELAKDPR IAA TMENAQ KGEIMPNIPQ MSAFWYAVRT AVINAASGRQ TVDEALKDAQ TNSSSNNNNN NNNNNLGLEV LFQGPVSSHF QELS IYQDQ EQRILKFLEE LGEGKATTAH DLSGKLGTPK KEINRVLYSL AKKGKLQKEA GTPPLWKIAV STQAWNQHSG VVRPD GHSQ GAPNSDPSLE PEDRNSTSVS EDLLEPFIAV SAQAWNQHSG VVRPDSHSQG SPNSDPGLEP EDSNSTSALE DPLEFL DMA EIKEKICDYL FNVSDSSALN LAKNIGLTKA RDINAVLIDM ERQGDVYRQG TTPPIWHLTD KKRERMQIKR NTNSVPE TA PAAIPETKRN AEFLTCNIPT SNASNNMVTT EKVENGQEPV IKLENRQEAR PEPARLKPPV HYNGPSKAGY VDFENGQW A TDDIPDDLNS IRAAPGEFRA IMEMPSFYSH GLPRCSPYKK LTECQLKNPI SGLLEYAQFA SQTCEFNMIE QSGPPHEPR FKFQVVINGR EFPPAEAGSK KVAKQDAAMK AMTILLEEAK AKDSGKSEES SHYSTEKESE KTAESQTPTP SATSFFSGKS PVTTLLECM HKLGNSCEFR LLSKEGPAHE PKFQYCVAVG AQTFPSVSAP SKKVAKQMAA EEAMKALHGE ATNSMASDNQ P EGMISESL DNLESMMPNK VRKIGELVRY LNTNPVGGLL EYARSHGFAA EFKLVDQSGP PHEPKFVYQA KVGGRWFPAV CA HSKKQGK QEAADAALRV LIGENEKAER MGFTEVTPVT GASLRRTMLL LSRSPEAQPK TLPLTGSTFH DQIAMLSHRC FNT LTNSFQ PSLLGRKILA AIIMKKDSED MGVVVSLGTG NRCVKGDSLS LKGETVNDCH AEIISRRGFI RFLYSELMKY NSQT AKDSI FEPAKGGEKL QIKKTVSFHL YISTAPCGDG ALFDKSCSDR AMESTESRHY PVFENPKQGK LRTKVENGEG TIPVE SSDI VPTWDGIRLG ERLRTMSCSD KILRWNVLGL QGALLTHFLQ PIYLKSVTLG YLFSQGHLTR AICCRVTRDG SAFEDG LRH PFIVNHPKVG RVSIYDSKRQ SGKTKETSVN WCLADGYDLE ILDGTRGTVD GPRNELSRVS KKNIFLLFKK LCSFRYR RD LLRLSYGEAK KAARDYETAK NYFKKGLKDM GYGNWISKPQ EEKNFYLCPV

UniProtKB: Maltodextrin-binding protein, Double-stranded RNA-specific adenosine deaminase

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Macromolecule #2: RNA (66-MER)

MacromoleculeName: RNA (66-MER) / type: rna / ID: 2 / Number of copies: 1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 21.105449 KDa
SequenceString:
GGGCU(8AZ)UUCG UUUUCCUAUU GAGCAUAGCC GCUUCUUCGG CUAUGCUCAA UAGGAAAACG AACAGU

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Macromolecule #3: INOSITOL HEXAKISPHOSPHATE

MacromoleculeName: INOSITOL HEXAKISPHOSPHATE / type: ligand / ID: 3 / Number of copies: 2 / Formula: IHP
Molecular weightTheoretical: 660.035 Da
Chemical component information

ChemComp-IHP:
INOSITOL HEXAKISPHOSPHATE

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Macromolecule #4: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 4 / Number of copies: 4 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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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: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TECNAI 20
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: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.2 µm / Nominal defocus min: 0.8 µm

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 144772
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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