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- PDB-9tgm: Cryo-EM structure of MCM2-7 DH bound to Sld3-Sld7 -

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Basic information

Entry
Database: PDB / ID: 9tgm
TitleCryo-EM structure of MCM2-7 DH bound to Sld3-Sld7
Components
  • (DNA replication licensing factor ...) x 5
  • DNA replication regulator SLD3
  • Minichromosome maintenance protein 5
  • Mitochondrial morphogenesis protein SLD7
KeywordsREPLICATION / Helicase / Activation / Phosphorylation
Function / homology
Function and homology information


regulation of mitotic DNA replication initiation / MCM core complex / Assembly of the pre-replicative complex / Switching of origins to a post-replicative state / nuclear DNA replication / MCM complex binding / premeiotic DNA replication / pre-replicative complex assembly involved in nuclear cell cycle DNA replication / Activation of the pre-replicative complex / CMG complex ...regulation of mitotic DNA replication initiation / MCM core complex / Assembly of the pre-replicative complex / Switching of origins to a post-replicative state / nuclear DNA replication / MCM complex binding / premeiotic DNA replication / pre-replicative complex assembly involved in nuclear cell cycle DNA replication / Activation of the pre-replicative complex / CMG complex / nuclear pre-replicative complex / Activation of ATR in response to replication stress / DNA replication preinitiation complex / single-stranded DNA helicase activity / mitotic DNA replication checkpoint signaling / MCM complex / mitotic DNA replication initiation / mitotic DNA replication / silent mating-type cassette heterochromatin formation / double-strand break repair via break-induced replication / DNA strand elongation involved in DNA replication / nuclear replication fork / DNA replication origin binding / subtelomeric heterochromatin formation / chromosome, centromeric region / DNA replication initiation / regulation of DNA-templated DNA replication initiation / helicase activity / transcription elongation by RNA polymerase II / nuclear envelope / peroxisome / single-stranded DNA binding / spindle pole / heterochromatin formation / DNA helicase / DNA replication / DNA helicase activity / chromosome, telomeric region / chromatin binding / DNA damage response / chromatin / endoplasmic reticulum / ATP hydrolysis activity / nucleoplasm / ATP binding / nucleus / cytoplasm
Similarity search - Function
Mitochondrial morphogenesis protein Sld7 / Sld7 C-terminal domain / Sld7, N-terminal / Sld7 C-terminal domain / Mitochondrial morphogenesis protein SLD7 N-terminal domain / Sld3, N-terminal / Sld3 N-terminal domain / DNA replication regulator Sld3, C-terminal / DNA replication regulator Sld3 / DNA replication regulator SLD3, STD domain ...Mitochondrial morphogenesis protein Sld7 / Sld7 C-terminal domain / Sld7, N-terminal / Sld7 C-terminal domain / Mitochondrial morphogenesis protein SLD7 N-terminal domain / Sld3, N-terminal / Sld3 N-terminal domain / DNA replication regulator Sld3, C-terminal / DNA replication regulator Sld3 / DNA replication regulator SLD3, STD domain / : / MCM3 winged helix domain / : / MCM5, C-terminal domain / DNA replication licensing factor MCM7, winged helix / : / DNA replication licensing factor Mcm5 / MCM4, winged helix domain / Mini-chromosome maintenance complex protein 4 / DNA replication licensing factor Mcm3 / : / MCM3-like, winged helix domain / DNA replication licensing factor Mcm6 / DNA replication licensing factor Mcm7 / Mcm6, C-terminal winged-helix domain / MCM6 C-terminal winged-helix domain / DNA replication licensing factor Mcm2 / Mini-chromosome maintenance protein 2 / Mini-chromosome maintenance, conserved site / MCM family signature. / MCM N-terminal domain / MCM N-terminal domain / MCM OB domain / MCM OB domain / Mini-chromosome maintenance protein / MCM, AAA-lid domain / MCM P-loop domain / MCM AAA-lid domain / MCM family C-terminal AAA(+) ATPase domain (MCM-CTD) profile. / minichromosome maintenance proteins / MCM domain / Winged helix-like DNA-binding domain superfamily / Nucleic acid-binding, OB-fold / ATPases associated with a variety of cellular activities / AAA+ ATPase domain / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
ADENOSINE-5'-DIPHOSPHATE / DNA replication licensing factor MCM3 / DNA replication licensing factor MCM2 / Minichromosome maintenance protein 5 / DNA replication licensing factor MCM4 / DNA replication licensing factor MCM7 / DNA replication licensing factor MCM6 / DNA replication regulator SLD3 / Mitochondrial morphogenesis protein SLD7
Similarity search - Component
Biological speciesSaccharomyces cerevisiae (brewer's yeast)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.6 Å
AuthorsSaleh, A. / Noguchi, Y. / Ivanova, M.E. / Aramayo, R. / Speck, C.
Funding support United Kingdom, 4items
OrganizationGrant numberCountry
Wellcome Trust107903/Z/15/Z United Kingdom
Biotechnology and Biological Sciences Research Council (BBSRC)BB/T005378/1 United Kingdom
Cancer Research UKDRCNPG-May21/100006 United Kingdom
Wellcome Trust206175/Z/17/Z United Kingdom
CitationJournal: Nat Commun / Year: 2026
Title: Structural insights into Sld3-Sld7-dependent Cdc45 loading during replication initiation.
Authors: Yasunori Noguchi / Almutasem Saleh / Sarah Schneider / Marina E Ivanova / Zhuo Angel Chen / Lepakshi Ranjha / Ricardo Aramayo / Silvia Tognetti / Sarah V Faull / Juri Rappsilber / Christian Speck /
Abstract: Regulated helicase activation by DDK kinase is central for genome stability. However, how DDK phosphorylation primes the MCM2-7 double hexamer (DH) for Sld3-Sld7 binding and Cdc45 loading remained ...Regulated helicase activation by DDK kinase is central for genome stability. However, how DDK phosphorylation primes the MCM2-7 double hexamer (DH) for Sld3-Sld7 binding and Cdc45 loading remained unclear. We define this mechanism through cryo-EM structures of MCM2-7 DH-Sld3-Sld7 (MS) and MCM2-7 DH-Sld3-Sld7-Cdc45 (MSC). We reveal that the autoinhibitory Mcm4 tail engages not only Mcm4 but also Mcm6. Upon DDK-dependent phosphorylation, both of these sites become accessible. In the context of the MS structure, we identify that two short Sld3 motifs that contact Mcm4 and Mcm6 read out the DH phosphorylation state, while the Sld3 Treslin domain (STD) binds to Mcm2. In the MSC structure, Cdc45 dislodges the Sld3 STD from Mcm2, allowing Sld3 to position Cdc45 at the Mcm2/Mcm5 interface. Mutagenesis of the Sld3 STD-Cdc45 interface disrupts Cdc45 loading, validating this interaction. Together, our data reveal a phosphorylation-encoded mechanism coupling DDK-activated Mcm4/Mcm6 surfaces to distal Cdc45 placement, explaining how firing factors choreograph the DH-to-CMG transition.
History
DepositionDec 2, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 26, 2026Provider: repository / Type: Initial release
Revision 1.0Aug 26, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.1Sep 23, 2026Group: Data collection / Database references / Category: citation / em_admin
Item: _citation.journal_volume / _citation.pdbx_database_id_PubMed ..._citation.journal_volume / _citation.pdbx_database_id_PubMed / _citation.title / _em_admin.last_update
Revision 1.1Sep 23, 2026Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / Category: citation / em_admin
Data content type: EM metadata / EM metadata ...EM metadata / EM metadata / EM metadata / EM metadata
Item: _citation.journal_volume / _citation.pdbx_database_id_PubMed ..._citation.journal_volume / _citation.pdbx_database_id_PubMed / _citation.title / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
2: DNA replication licensing factor MCM2
3: DNA replication licensing factor MCM3
4: DNA replication licensing factor MCM4
5: Minichromosome maintenance protein 5
6: DNA replication licensing factor MCM6
7: DNA replication licensing factor MCM7
8: DNA replication regulator SLD3
B: DNA replication licensing factor MCM2
C: DNA replication licensing factor MCM3
D: DNA replication licensing factor MCM4
E: Minichromosome maintenance protein 5
F: DNA replication licensing factor MCM6
G: DNA replication licensing factor MCM7
X: DNA replication regulator SLD3
Y: Mitochondrial morphogenesis protein SLD7
hetero molecules


Theoretical massNumber of molelcules
Total (without water)1,401,26633
Polymers1,397,19515
Non-polymers4,07218
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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DNA replication licensing factor ... , 5 types, 10 molecules 2B3C4D6F7G

#1: Protein DNA replication licensing factor MCM2 / Minichromosome maintenance protein 2


Mass: 98911.539 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Saccharomyces cerevisiae (brewer's yeast)
Gene: MCM2, YBL023C, YBL0438 / Production host: Saccharomyces cerevisiae (brewer's yeast) / References: UniProt: P29469, DNA helicase
#2: Protein DNA replication licensing factor MCM3 / Minichromosome maintenance protein 3


Mass: 107653.508 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Saccharomyces cerevisiae (brewer's yeast)
Gene: MCM3, YEL032W, SYGP-ORF23 / Production host: Saccharomyces cerevisiae (brewer's yeast) / References: UniProt: P24279, DNA helicase
#3: Protein DNA replication licensing factor MCM4 / Cell division control protein 54


Mass: 105138.375 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Saccharomyces cerevisiae (brewer's yeast)
Gene: MCM4, CDC54, HCD21, YPR019W, YP9531.13 / Production host: Saccharomyces cerevisiae (brewer's yeast) / References: UniProt: P30665, DNA helicase
#5: Protein DNA replication licensing factor MCM6 / Minichromosome maintenance protein 6


Mass: 113110.211 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Saccharomyces cerevisiae (brewer's yeast)
Gene: MCM6, YGL201C / Production host: Saccharomyces cerevisiae (brewer's yeast) / References: UniProt: P53091, DNA helicase
#6: Protein DNA replication licensing factor MCM7 / Cell division control protein 47 / Minichromosome maintenance protein 7


Mass: 95049.875 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Saccharomyces cerevisiae (brewer's yeast)
Gene: MCM7, CDC47, YBR202W, YBR1441 / Production host: Saccharomyces cerevisiae (brewer's yeast) / References: UniProt: P38132, DNA helicase

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Protein , 3 types, 5 molecules 5E8XY

#4: Protein Minichromosome maintenance protein 5 / Cell division control protein 46


Mass: 86505.734 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Saccharomyces cerevisiae (brewer's yeast)
Gene: MCM5, CDC46, YLR274W, L9328.1 / Production host: Saccharomyces cerevisiae (brewer's yeast) / References: UniProt: P29496, DNA helicase
#7: Protein DNA replication regulator SLD3


Mass: 77428.633 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Saccharomyces cerevisiae (brewer's yeast)
Gene: SLD3, YGL113W, G2980 / Production host: Saccharomyces cerevisiae (brewer's yeast) / References: UniProt: P53135
#8: Protein Mitochondrial morphogenesis protein SLD7 / Synthetic lethality with DPB11-24 mutation protein 7


Mass: 29598.828 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Saccharomyces cerevisiae (brewer's yeast)
Gene: SLD7, YOR060C, YOR29-11 / Production host: Saccharomyces cerevisiae (brewer's yeast) / References: UniProt: Q08457

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Non-polymers , 2 types, 18 molecules

#9: Chemical
ChemComp-ADP / ADENOSINE-5'-DIPHOSPHATE


Mass: 427.201 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C10H15N5O10P2 / Feature type: SUBJECT OF INVESTIGATION / Comment: ADP, energy-carrying molecule*YM
#10: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 10 / Source method: obtained synthetically / Formula: Zn / Feature type: SUBJECT OF INVESTIGATION

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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

ComponentName: MCM2-7 DH bound to Sld3-Sld7 / Type: COMPLEX / Entity ID: #1-#8 / Source: RECOMBINANT
Molecular weightValue: 1.5 MDa / Experimental value: NO
Source (natural)Organism: Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (yeast)
Source (recombinant)Organism: Saccharomyces cerevisiae (brewer's yeast)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R2/2
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K
Details: Wait time: 30 s Blotting time: 1.5 s Blot force: +2

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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: 81000 X / Nominal defocus max: 3200 nm / Nominal defocus min: 1000 nm / Cs: 2.7 mm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 50.4 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 29592

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Processing

EM software
IDNameVersionCategoryDetails (eV)
1Topazparticle selection
2PHENIX1.21.2_5419model refinement
3EPUimage acquisition
5CTFFIND4.1.14CTF correction
10RELION4initial Euler assignment
11cryoSPARC4.6.2final Euler assignment
12cryoSPARC4.6.2classification
13cryoSPARC4.6.23D reconstruction
14RELION43D reconstructionpost-process
15PHENIX1.21.2_54193D reconstructionphenix.combine_focused_maps
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 344362
Details: For the composite MS map, resolution was estimated with phenix.mtriage, using the unmasked model-map FSC, which gave an FSC(0.143) resolution of 3.6 Angstrom. Final focused refinement ...Details: For the composite MS map, resolution was estimated with phenix.mtriage, using the unmasked model-map FSC, which gave an FSC(0.143) resolution of 3.6 Angstrom. Final focused refinement particle subsets used to generate composite map (344,362 particles): DH core (66,052 particles) Sld3 MRD1:Mcm6 (63,192 particles) Sld3 MRD2:Mcm4 (166,980 particles) Sld7:Mcm6 (48,138 particles)
Symmetry type: POINT
Atomic model building
IDPDB-ID 3D fitting-IDAccession codeInitial refinement model-IDSource nameType
17PT6

7pt6

17PT61PDBexperimental model
27P30

7p30

17P302PDBexperimental model
35BK4

5bk4

15BK43PDBexperimental model
43WI3

3wi3

13WI34PDBexperimental model
53X38

3x38

13X385PDBexperimental model
RefinementHighest resolution: 3.6 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00464074
ELECTRON MICROSCOPYf_angle_d0.67486658
ELECTRON MICROSCOPYf_dihedral_angle_d5.8318769
ELECTRON MICROSCOPYf_chiral_restr0.04510059
ELECTRON MICROSCOPYf_plane_restr0.00511168

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