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- EMDB-61113: Cryo-EM structure of NAT10 with Co-enzyme A -

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Basic information

Entry
Database: EMDB / ID: EMD-61113
TitleCryo-EM structure of NAT10 with Co-enzyme A
Map data
Sample
  • Complex: NAT10 with Co-enzyme A
    • Protein or peptide: RNA cytidine acetyltransferase
  • Ligand: COENZYME A
KeywordsNAT10 / acyltransferase / N4-acetylcytidine / TRANSFERASE
Function / homology
Function and homology information


mRNA N-acetyltransferase activity / tRNA wobble cytosine modification / tRNA cytidine N4-acetyltransferase activity / rRNA acetylation involved in maturation of SSU-rRNA / 18S rRNA cytidine N-acetyltransferase activity / tRNA acetylation / rRNA modification / regulation of centrosome duplication / N-acetyltransferase activity / telomerase holoenzyme complex ...mRNA N-acetyltransferase activity / tRNA wobble cytosine modification / tRNA cytidine N4-acetyltransferase activity / rRNA acetylation involved in maturation of SSU-rRNA / 18S rRNA cytidine N-acetyltransferase activity / tRNA acetylation / rRNA modification / regulation of centrosome duplication / N-acetyltransferase activity / telomerase holoenzyme complex / rRNA modification in the nucleus and cytosol / protein acetylation / negative regulation of telomere maintenance via telomerase / DNA polymerase binding / Transferases; Acyltransferases; Transferring groups other than aminoacyl groups / positive regulation of translation / small-subunit processome / regulation of translation / ribosomal small subunit biogenesis / midbody / tRNA binding / chromosome, telomeric region / nucleolus / RNA binding / nucleoplasm / ATP binding / nucleus / membrane
Similarity search - Function
Possible tRNA binding domain / RNA cytidine acetyltransferase NAT10 / Possible tRNA binding domain / Helicase domain / tRNA(Met) cytidine acetyltransferase TmcA, N-terminal / TmcA/NAT10/Kre33 / RNA cytidine acetyltransferase NAT10/TcmA, helicase domain / tRNA(Met) cytidine acetyltransferase TmcA, N-terminal / GNAT acetyltransferase 2 / Gcn5-related N-acetyltransferase (GNAT) domain profile. ...Possible tRNA binding domain / RNA cytidine acetyltransferase NAT10 / Possible tRNA binding domain / Helicase domain / tRNA(Met) cytidine acetyltransferase TmcA, N-terminal / TmcA/NAT10/Kre33 / RNA cytidine acetyltransferase NAT10/TcmA, helicase domain / tRNA(Met) cytidine acetyltransferase TmcA, N-terminal / GNAT acetyltransferase 2 / Gcn5-related N-acetyltransferase (GNAT) domain profile. / GNAT domain / Acyl-CoA N-acyltransferase / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
RNA cytidine acetyltransferase
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsJiang Y / Xia J
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: Drug Resist Updat / Year: 2025
Title: Targeting NAT10 attenuates homologous recombination via destabilizing DNA:RNA hybrids and overcomes PARP inhibitor resistance in cancers.
Authors: Zhu Xu / Mingming Zhu / Longpo Geng / Jun Zhang / Jing Xia / Qiang Wang / Hongda An / Anliang Xia / Yuanyuan Yu / Shihan Liu / Junjie Tong / Wei-Guo Zhu / Yiyang Jiang / Beicheng Sun /
Abstract: AIMS: RNA metabolism has been extensively studied in DNA double-strand break (DSB) repair. The RNA acetyltransferase N-acetyltransferase 10 (NAT10)-mediated N4-acetylcytidine (ac4C) modification in ...AIMS: RNA metabolism has been extensively studied in DNA double-strand break (DSB) repair. The RNA acetyltransferase N-acetyltransferase 10 (NAT10)-mediated N4-acetylcytidine (ac4C) modification in DSB repair remains largely elusive. In this study, we aim to decipher the role for ac4C modification by NAT10 in DSB repair in hepatocellular carcinoma (HCC).
METHODS: Laser micro-irradiation and chromatin immunoprecipitation (ChIP) were used to assess the accumulation of ac4C modification and NAT10 at DSB sites. Cryo-electron microscopy (cryo-EM) was used ...METHODS: Laser micro-irradiation and chromatin immunoprecipitation (ChIP) were used to assess the accumulation of ac4C modification and NAT10 at DSB sites. Cryo-electron microscopy (cryo-EM) was used to determine the structures of NAT10 in complex with its inhibitor, remodelin. Hepatocyte-specific deletion of NAT10 mouse models were adopted to detect the effects of NAT10 on HCC progression. Subcutaneous xenograft, human HCC organoid and patient-derived xenograft (PDX) model were exploited to determine the therapy efficiency of the combination of a poly (ADP-ribose) polymerase 1 (PARP1) inhibitor (PARPi) and remodelin.
RESULTS: NAT10 promptly accumulates at DSB sites, where it executes ac4C modification on RNAs at DNA:RNA hybrids dependent on PARP1. This in turn enhances the stability of DNA:RNA hybrids and ...RESULTS: NAT10 promptly accumulates at DSB sites, where it executes ac4C modification on RNAs at DNA:RNA hybrids dependent on PARP1. This in turn enhances the stability of DNA:RNA hybrids and promotes homologous recombination (HR) repair. The ablation of NAT10 curtails HCC progression. Furthermore, the cryo-EM yields a remarkable 2.9 angstroms resolution structure of NAT10-remodelin, showcasing a C2 symmetric architecture. Remodelin treatment significantly enhanced the sensitivity of HCC cells to a PARPi and targeting NAT10 also restored sensitivity to a PARPi in ovarian and breast cancer cells that had developed resistance.
CONCLUSION: Our study elucidated the mechanism of NAT10-mediated ac4C modification in DSB repair, revealing that targeting NAT10 confers synthetic lethality to PARP inhibition in HCC. Our findings ...CONCLUSION: Our study elucidated the mechanism of NAT10-mediated ac4C modification in DSB repair, revealing that targeting NAT10 confers synthetic lethality to PARP inhibition in HCC. Our findings suggest that co-inhibition of NAT10 and PARP1 is an effective novel therapeutic strategy for patients with HCC and have the potential to overcome PARPi resistance.
History
DepositionAug 8, 2024-
Header (metadata) releaseApr 23, 2025-
Map releaseApr 23, 2025-
UpdateApr 23, 2025-
Current statusApr 23, 2025Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_61113.png

Downloads & links

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Map

FileDownload / File: emd_61113.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

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AxesZ (Sec.)Y (Row.)X (Col.)
0.81 Å/pix.
x 320 pix.
= 259.2 Å		0.81 Å/pix.
x 320 pix.
= 259.2 Å		0.81 Å/pix.
x 320 pix.
= 259.2 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.81 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.24
Minimum - Maximum-1.9626243 - 3.1102133
Average (Standard dev.)-0.0002611602 (±0.06481757)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 259.2 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_61113_half_map_1.map
Projections & Slices
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Half map: #1

Fileemd_61113_half_map_2.map
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Sample components

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Entire : NAT10 with Co-enzyme A

EntireName: NAT10 with Co-enzyme A
Components
  • Complex: NAT10 with Co-enzyme A
    • Protein or peptide: RNA cytidine acetyltransferase
  • Ligand: COENZYME A

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Supramolecule #1: NAT10 with Co-enzyme A

SupramoleculeName: NAT10 with Co-enzyme A / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: RNA cytidine acetyltransferase

MacromoleculeName: RNA cytidine acetyltransferase / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
EC number: Transferases; Acyltransferases; Transferring groups other than aminoacyl groups
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 103.855844 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MHRKKVDNRI RILIENGVAE RQRSLFVVVG DRGKDQVVIL HHMLSKATVK ARPSVLWCYK KELGFSSHRK KRMRQLQKKI KNGTLNIKQ DDPFELFIAA TNIRYCYYNE THKILGNTFG MCVLQDFEAL TPNLLARTVE TVEGGGLVVI LLRTMNSLKQ L YTVTMDVH ...String:
MHRKKVDNRI RILIENGVAE RQRSLFVVVG DRGKDQVVIL HHMLSKATVK ARPSVLWCYK KELGFSSHRK KRMRQLQKKI KNGTLNIKQ DDPFELFIAA TNIRYCYYNE THKILGNTFG MCVLQDFEAL TPNLLARTVE TVEGGGLVVI LLRTMNSLKQ L YTVTMDVH SRYRTEAHQD VVGRFNERFI LSLASCKKCL VIDDQLNILP ISSHVATMEA LPPQTPDESL GPSDLELREL KE SLQDTQP VGVLVDCCKT LDQAKAVLKF IEGISEKTLR STVALTAARG RGKSAALGLA IAGAVAFGYS NIFVTSPSPD NLH TLFEFV FKGFDALQYQ EHLDYEIIQS LNPEFNKAVI RVNVFREHRQ TIQYIHPADA VKLGQAELVV IDEAAAIPLP LVKS LLGPY LVFMASTING YEGTGRSLSL KLIQQLRQQS AQSQVSTTAE NKTTTTARLA SARTLYEVSL QESIRYAPGD AVEKW LNDL LCLDCLNITR IVSGCPLPEA CELYYVNRDT LFCYHKASEV FLQRLMALYV ASHYKNSPND LQMLSDAPAH HLFCLL PPV PPTQNALPEV LAVIQVCLEG EISRQSILNS LSRGKKASGD LIPWTVSEQF QDPDFGGLSG GRVVRIAVHP DYQGMGY GS RALQLLQMYY EGRFPCLEEK VLETPQEIHT VSSEAVSLLE EVITPRKDLP PLLLKLNERP AERLDYLGVS YGLTPRLL K FWKRAGFVPV YLRQTPNDLT GEHSCIMLKT LTDEDEADQG GWLAAFWKDF RRRFLALLSY QFSTFSPSLA LNIIQNRNM GKPAQPALSR EELEALFLPY DLKRLEMYSR NMVDYHLIMD MIPAISRIYF LNQLGDLALS AAQSALLLGI GLQHKSVDQL EKEIELPSG QLMGLFNRII RKVVKLFNEV QEKAIEEQMV AAK

UniProtKB: RNA cytidine acetyltransferase

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Macromolecule #2: COENZYME A

MacromoleculeName: COENZYME A / type: ligand / ID: 2 / Number of copies: 2 / Formula: COA
Molecular weightTheoretical: 767.534 Da
Chemical component information

ChemComp-COA:
COENZYME A

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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 mg/mL
BufferpH: 7.4 / Details: 20mM Hepes, 150 mM NaCl, 5% Glycerol, pH 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: FEI FALCON I (4k x 4k) / Average electron dose: 49.81 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: SPOT SCAN / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.2 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 91734
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: NOT APPLICABLE

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