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- PDB-9j3c: Cryo-EM structure of NAT10 with Co-enzyme A -

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Basic information

Entry
Database: PDB / ID: 9j3c
TitleCryo-EM structure of NAT10 with Co-enzyme A
ComponentsRNA cytidine acetyltransferase
KeywordsTRANSFERASE / NAT10 / acyltransferase / N4-acetylcytidine
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
COENZYME A / RNA cytidine acetyltransferase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsJiang, Y. / Xia, J.
Funding support1items
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, 2024Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Apr 23, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: RNA cytidine acetyltransferase
B: RNA cytidine acetyltransferase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)209,2474
Polymers207,7122
Non-polymers1,5352
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein RNA cytidine acetyltransferase / 18S rRNA cytosine acetyltransferase / N-acetyltransferase 10 / N-acetyltransferase-like protein / hALP


Mass: 103855.844 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NAT10, ALP, KIAA1709 / Production host: Homo sapiens (human)
References: UniProt: Q9H0A0, Transferases; Acyltransferases; Transferring groups other than aminoacyl groups
#2: Chemical ChemComp-COA / COENZYME A


Mass: 767.534 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H36N7O16P3S / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationN

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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: NAT10 with Co-enzyme A / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4 / Details: 20mM Hepes, 150 mM NaCl, 5% Glycerol, pH 7.4
SpecimenConc.: 2 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: SPOT SCAN
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 49.81 e/Å2 / Film or detector model: FEI FALCON I (4k x 4k)

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Processing

EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 91734 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 68.53 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.001812506
ELECTRON MICROSCOPYf_angle_d0.507416986
ELECTRON MICROSCOPYf_chiral_restr0.03931979
ELECTRON MICROSCOPYf_plane_restr0.00512150
ELECTRON MICROSCOPYf_dihedral_angle_d4.72981745

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