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- PDB-9iin: Structure of CTF18-PCNA with ATP and Mg2+ -

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Basic information

Entry
Database: PDB / ID: 9iin
TitleStructure of CTF18-PCNA with ATP and Mg2+
Components
  • (Replication factor C subunit ...) x 4
  • Chromosome transmission fidelity protein 18 homolog
  • Proliferating cell nuclear antigen
KeywordsDNA BINDING PROTEIN / CTF18-RFC / human clamp loader / PCNA / sliding clamp / complex / ATP
Function / homology
Function and homology information


Elg1 RFC-like complex / DNA replication factor C complex / Ctf18 RFC-like complex / positive regulation of deoxyribonuclease activity / dinucleotide insertion or deletion binding / PCNA-p21 complex / mitotic telomere maintenance via semi-conservative replication / purine-specific mismatch base pair DNA N-glycosylase activity / DNA clamp loader activity / nuclear lamina ...Elg1 RFC-like complex / DNA replication factor C complex / Ctf18 RFC-like complex / positive regulation of deoxyribonuclease activity / dinucleotide insertion or deletion binding / PCNA-p21 complex / mitotic telomere maintenance via semi-conservative replication / purine-specific mismatch base pair DNA N-glycosylase activity / DNA clamp loader activity / nuclear lamina / positive regulation of DNA-directed DNA polymerase activity / Polymerase switching / MutLalpha complex binding / Telomere C-strand (Lagging Strand) Synthesis / Processive synthesis on the lagging strand / PCNA complex / Removal of the Flap Intermediate / Processive synthesis on the C-strand of the telomere / Polymerase switching on the C-strand of the telomere / Mismatch repair (MMR) directed by MSH2:MSH3 (MutSbeta) / Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha) / Transcription of E2F targets under negative control by DREAM complex / Removal of the Flap Intermediate from the C-strand / replisome / response to L-glutamate / HDR through Single Strand Annealing (SSA) / DNA strand elongation involved in DNA replication / response to dexamethasone / DNA synthesis involved in DNA repair / Impaired BRCA2 binding to RAD51 / histone acetyltransferase binding / DNA polymerase processivity factor activity / G1/S-Specific Transcription / leading strand elongation / nuclear replication fork / replication fork processing / Presynaptic phase of homologous DNA pairing and strand exchange / SUMOylation of DNA replication proteins / PCNA-Dependent Long Patch Base Excision Repair / ATP-dependent activity, acting on DNA / response to cadmium ion / translesion synthesis / estrous cycle / mismatch repair / Activation of ATR in response to replication stress / cyclin-dependent protein kinase holoenzyme complex / base-excision repair, gap-filling / DNA polymerase binding / liver regeneration / epithelial cell differentiation / positive regulation of DNA repair / TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest / Translesion synthesis by REV1 / Translesion synthesis by POLK / Translesion synthesis by POLI / positive regulation of DNA replication / Gap-filling DNA repair synthesis and ligation in GG-NER / replication fork / nuclear estrogen receptor binding / male germ cell nucleus / Termination of translesion DNA synthesis / Recognition of DNA damage by PCNA-containing replication complex / Translesion Synthesis by POLH / receptor tyrosine kinase binding / G2/M DNA damage checkpoint / HDR through Homologous Recombination (HRR) / Dual Incision in GG-NER / DNA-templated DNA replication / cellular response to xenobiotic stimulus / cellular response to hydrogen peroxide / Dual incision in TC-NER / Gap-filling DNA repair synthesis and ligation in TC-NER / cellular response to UV / response to estradiol / E3 ubiquitin ligases ubiquitinate target proteins / heart development / chromatin organization / Processing of DNA double-strand break ends / Regulation of TP53 Activity through Phosphorylation / damaged DNA binding / chromosome, telomeric region / DNA replication / nuclear body / DNA repair / centrosome / chromatin binding / chromatin / protein-containing complex binding / enzyme binding / negative regulation of transcription by RNA polymerase II / ATP hydrolysis activity / DNA binding / extracellular exosome / nucleoplasm / ATP binding / identical protein binding / nucleus / membrane / cytosol
Similarity search - Function
: / Replication factor C subunit 3, C-terminal domain / RCF1/5-like, AAA+ ATPase lid domain / Replication factor C, C-terminal / Replication factor C C-terminal domain / : / DNA polymerase III, delta subunit / : / DNA polymerase III, clamp loader complex, gamma/delta/delta subunit, C-terminal / Proliferating cell nuclear antigen signature 2. ...: / Replication factor C subunit 3, C-terminal domain / RCF1/5-like, AAA+ ATPase lid domain / Replication factor C, C-terminal / Replication factor C C-terminal domain / : / DNA polymerase III, delta subunit / : / DNA polymerase III, clamp loader complex, gamma/delta/delta subunit, C-terminal / Proliferating cell nuclear antigen signature 2. / Proliferating cell nuclear antigen, PCNA, conserved site / Proliferating cell nuclear antigen signature 1. / Proliferating cell nuclear antigen, PCNA / Proliferating cell nuclear antigen, PCNA, N-terminal / Proliferating cell nuclear antigen, PCNA, C-terminal / Proliferating cell nuclear antigen, N-terminal domain / Proliferating cell nuclear antigen, C-terminal domain / : / ATPase family associated with various cellular activities (AAA) / ATPase, AAA-type, core / ATPases associated with a variety of cellular activities / AAA+ ATPase domain / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
ADENOSINE-5'-DIPHOSPHATE / ADENOSINE-5'-TRIPHOSPHATE / Proliferating cell nuclear antigen / Replication factor C subunit 4 / Replication factor C subunit 2 / Replication factor C subunit 5 / Replication factor C subunit 3 / Chromosome transmission fidelity protein 18 homolog
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsBriola, G.R. / Tehseen, M. / Al-Amodi, A. / Nguyen, P.Q. / Savva, C.G. / Hamdan, S.M. / De Biasio, A.
Funding support1items
OrganizationGrant numberCountry
Other government
CitationJournal: bioRxiv / Year: 2025
Title: Structure of the human CTF18-RFC clamp loader bound to PCNA.
Authors: Giuseppina R Briola / Muhammad Tehseen / Amani Al-Amodi / Grace Young / Ammar U Danazumi / Phong Quoc Nguyen / Christos G Savva / Mark Hedglin / Samir M Hamdan / Alfredo De Biasio /
Abstract: Sliding clamps like PCNA are crucial processivity factors for replicative polymerases, requiring specific clamp loaders for loading onto DNA. The human alternative clamp loader CTF18-RFC interacts ...Sliding clamps like PCNA are crucial processivity factors for replicative polymerases, requiring specific clamp loaders for loading onto DNA. The human alternative clamp loader CTF18-RFC interacts with the leading strand polymerase Pol ε and loads PCNA onto primer/template DNA using its RFC pentameric module. Here, we provide a structural characterization of the human CTF18-RFC complex and its interaction with PCNA. Our cryo-EM data support that the Ctf8 and Dcc1 subunits of CTF18-RFC, which form the regulatory module interacting with Pol ε, are flexibly tethered to the RFC module. A 2.9 Å cryo-EM structure shows the RFC module bound to PCNA in an auto-inhibited conformation similar to the canonical RFC loader, marking the initial step of the clamp-loading reaction. The unique RFC1 (Ctf18) large subunit of CTF18-RFC, which based on the cryo-EM map shows high relative flexibility, is anchored to PCNA through an atypical low-affinity PIP box in the AAA+ domain and engages the RFC5 subunit using a novel β-hairpin at the disordered N-terminus. We show that deletion of this β-hairpin impairs the CTF18-RFC-PCNA complex stability, slows down clamp loading, and decreases the rate of primer synthesis by Pol ε. Our research identifies distinctive structural characteristics of the human CTF18-RFC complex, providing insights into its role in PCNA loading and the stimulation of leading strand synthesis by Pol ε.
History
DepositionJun 20, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jun 25, 2025Provider: repository / Type: Initial release
Revision 1.0Jun 25, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jun 25, 2025Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Jun 25, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jun 25, 2025Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jun 25, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jun 25, 2025Data content type: Mask / Part number: 1 / Data content type: Mask / Provider: repository / Type: Initial release
Revision 1.0Jun 25, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Aug 27, 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_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Chromosome transmission fidelity protein 18 homolog
B: Replication factor C subunit 2
C: Replication factor C subunit 5
D: Replication factor C subunit 4
E: Replication factor C subunit 3
F: Proliferating cell nuclear antigen
G: Proliferating cell nuclear antigen
H: Proliferating cell nuclear antigen
hetero molecules


Theoretical massNumber of molelcules
Total (without water)361,17814
Polymers359,1818
Non-polymers1,9976
Water00
1


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

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Components

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Protein , 2 types, 4 molecules AFGH

#1: Protein Chromosome transmission fidelity protein 18 homolog / hCTF18 / CHL12


Mass: 111407.070 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: -35: initiating methionine -34 to 0: expression tag
Source: (gene. exp.) Homo sapiens (human) / Gene: CHTF18, C16orf41, CTF18 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q8WVB6
#6: Protein Proliferating cell nuclear antigen / PCNA / Cyclin


Mass: 29617.672 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Details: -5: INITIATING METHIONINE -4 TO 0: EXPRESSION TAG / Source: (gene. exp.) Homo sapiens (human) / Gene: PCNA / Production host: Escherichia coli (E. coli) / References: UniProt: P12004

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Replication factor C subunit ... , 4 types, 4 molecules BCDE

#2: Protein Replication factor C subunit 2 / Activator 1 40 kDa subunit / A1 40 kDa subunit / Activator 1 subunit 2 / Replication factor C 40 ...Activator 1 40 kDa subunit / A1 40 kDa subunit / Activator 1 subunit 2 / Replication factor C 40 kDa subunit / RF-C 40 kDa subunit / RFC40


Mass: 39203.207 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RFC2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P35250
#3: Protein Replication factor C subunit 5 / Activator 1 36 kDa subunit / A1 36 kDa subunit / Activator 1 subunit 5 / Replication factor C 36 ...Activator 1 36 kDa subunit / A1 36 kDa subunit / Activator 1 subunit 5 / Replication factor C 36 kDa subunit / RF-C 36 kDa subunit / RFC36


Mass: 38545.512 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RFC5 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P40937
#4: Protein Replication factor C subunit 4 / Activator 1 37 kDa subunit / A1 37 kDa subunit / Activator 1 subunit 4 / Replication factor C 37 ...Activator 1 37 kDa subunit / A1 37 kDa subunit / Activator 1 subunit 4 / Replication factor C 37 kDa subunit / RF-C 37 kDa subunit / RFC37


Mass: 39735.711 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RFC4 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P35249
#5: Protein Replication factor C subunit 3 / Activator 1 38 kDa subunit / A1 38 kDa subunit / Activator 1 subunit 3 / Replication factor C 38 ...Activator 1 38 kDa subunit / A1 38 kDa subunit / Activator 1 subunit 3 / Replication factor C 38 kDa subunit / RF-C 38 kDa subunit / RFC38


Mass: 41436.258 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: -5: INITIATING METHIONINE -4 TO 0: EXPRESSION TAG / Source: (gene. exp.) Homo sapiens (human) / Gene: RFC3 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P40938

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Non-polymers , 3 types, 6 molecules

#7: Chemical ChemComp-ATP / ADENOSINE-5'-TRIPHOSPHATE


Mass: 507.181 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C10H16N5O13P3 / Feature type: SUBJECT OF INVESTIGATION / Comment: ATP, energy-carrying molecule*YM
#8: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg / Feature type: SUBJECT OF INVESTIGATION
#9: Chemical ChemComp-ADP / ADENOSINE-5'-DIPHOSPHATE


Mass: 427.201 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H15N5O10P2 / Feature type: SUBJECT OF INVESTIGATION / Comment: ADP, energy-carrying molecule*YM

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Details

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

Component
IDNameTypeDetailsEntity IDParent-IDSource
1CTF18-PCNACOMPLEXCTF18 in complex with PCNA, in presence of ATP and Mg2+#1-#60RECOMBINANT
2CTF18COMPLEX#1-#51RECOMBINANT
3PCNACOMPLEX#61RECOMBINANT
Molecular weightValue: 0.323 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
22Spodoptera frugiperda (fall armyworm)7108
33Escherichia coli (E. coli)562
Buffer solutionpH: 7.5 / Details: 50 mM Tris-HCl, 200 mM NaCl, 1 mM DTT
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: UltrAuFoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 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: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 130000 X / Nominal defocus max: 2700 nm / Nominal defocus min: 1500 nm / Cs: 2.7 mm / C2 aperture diameter: 50 µm / Alignment procedure: ZEMLIN TABLEAU
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Temperature (min): 83 K
Image recordingAverage exposure time: 5 sec. / Electron dose: 46 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 6181
EM imaging opticsEnergyfilter name: TFS Selectris X / Energyfilter slit width: 10 eV
Image scansSampling size: 14 µm / Width: 4096 / Height: 4096

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Processing

EM software
IDNameVersionCategory
1RELION4particle selection
2EPU3.5image acquisition
4RELION4CTF correction
7UCSF ChimeraXmodel fitting
9PHENIXmodel refinement
10RELION4initial Euler assignment
11RELION4final Euler assignment
13RELION43D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 3216167
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 602591 / Num. of class averages: 2 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT / Space: REAL
Atomic model buildingPDB-ID: 6VVO

6vvo


Accession code: 6VVO / Source name: PDB / Type: experimental model
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00320102
ELECTRON MICROSCOPYf_angle_d0.5827198
ELECTRON MICROSCOPYf_dihedral_angle_d5.8732727
ELECTRON MICROSCOPYf_chiral_restr0.0413170
ELECTRON MICROSCOPYf_plane_restr0.0043473

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