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- PDB-9qay: Catalytic core 1 of dimeric human telomerase -

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Basic information

Entry
Database: PDB / ID: 9qay
TitleCatalytic core 1 of dimeric human telomerase
Components
  • Adrenocortical dysplasia protein homolog
  • DNA (5'-D(P*GP*TP*TP*AP*GP*GP*G)-3')
  • Histone H2A
  • Histone H2B
  • Telomerase reverse transcriptase
  • hTR, human telomerase RNA (253-mer)
KeywordsDNA BINDING PROTEIN / Human telomerase catalytic core / reverse transcriptase / DNA substrate bound
Function / homology
Function and homology information


telomere assembly / positive regulation of hair cycle / template-free RNA nucleotidyltransferase activity / positive regulation of transdifferentiation / TERT-RMRP complex / DNA strand elongation / RNA-directed RNA polymerase complex / segmentation / siRNA transcription / urogenital system development ...telomere assembly / positive regulation of hair cycle / template-free RNA nucleotidyltransferase activity / positive regulation of transdifferentiation / TERT-RMRP complex / DNA strand elongation / RNA-directed RNA polymerase complex / segmentation / siRNA transcription / urogenital system development / positive regulation of protein localization to nucleolus / telomerase catalytic core complex / protection from non-homologous end joining at telomere / telomerase inhibitor activity / RNA-templated DNA biosynthetic process / establishment of protein localization to telomere / regulation of establishment of protein localization to telomere / telomerase activity / shelterin complex / Telomere C-strand synthesis initiation / Regulation of MITF-M-dependent genes involved in DNA replication, damage repair and senescence / siRNA processing / Telomere C-strand (Lagging Strand) Synthesis / nuclear telomere cap complex / telomere maintenance via recombination / positive regulation of vascular associated smooth muscle cell migration / telomere capping / telomerase holoenzyme complex / telomerase RNA binding / Processive synthesis on the C-strand of the telomere / Polymerase switching on the C-strand of the telomere / embryonic limb morphogenesis / Removal of the Flap Intermediate from the C-strand / protein localization to chromosome, telomeric region / DNA biosynthetic process / RNA-templated transcription / positive regulation of stem cell proliferation / telomeric DNA binding / negative regulation of telomere maintenance via telomerase / positive regulation of telomere maintenance / mitochondrial nucleoid / negative regulation of cellular senescence / replicative senescence / Telomere Extension By Telomerase / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / positive regulation of G1/S transition of mitotic cell cycle / response to cadmium ion / positive regulation of Wnt signaling pathway / positive regulation of protein binding / negative regulation of endothelial cell apoptotic process / telomere maintenance via telomerase / positive regulation of vascular associated smooth muscle cell proliferation / DNA polymerase binding / Packaging Of Telomere Ends / Recognition and association of DNA glycosylase with site containing an affected purine / Cleavage of the damaged purine / Recognition and association of DNA glycosylase with site containing an affected pyrimidine / Cleavage of the damaged pyrimidine / telomere maintenance / Inhibition of DNA recombination at telomere / Meiotic synapsis / skeletal system development / positive regulation of D-glucose import across plasma membrane / mitochondrion organization / intracellular protein transport / Formation of the beta-catenin:TCF transactivating complex / PML body / regulation of protein stability / DNA Damage/Telomere Stress Induced Senescence / positive regulation of miRNA transcription / RNA-directed DNA polymerase / transcription coactivator binding / RNA-directed DNA polymerase activity / protein import into nucleus / positive regulation of angiogenesis / structural constituent of chromatin / nucleosome / protein-folding chaperone binding / heart development / cellular response to hypoxia / negative regulation of neuron apoptotic process / tRNA binding / chromosome, telomeric region / nuclear speck / nuclear body / protein heterodimerization activity / RNA-directed RNA polymerase activity / protein-containing complex binding / nucleolus / protein homodimerization activity / DNA binding / RNA binding / nucleoplasm / metal ion binding / identical protein binding / nucleus / plasma membrane / cytosol
Similarity search - Function
Adrenocortical dysplasia protein / Shelterin complex subunit TPP1/Est3 / : / Shelterin complex subunit, TPP1/ACD / Telomerase reverse transcriptase, C-terminal extension / Telomerase ribonucleoprotein complex - RNA binding domain / Telomerase reverse transcriptase / Telomerase ribonucleoprotein complex - RNA-binding domain / Telomerase ribonucleoprotein complex - RNA binding domain / : ...Adrenocortical dysplasia protein / Shelterin complex subunit TPP1/Est3 / : / Shelterin complex subunit, TPP1/ACD / Telomerase reverse transcriptase, C-terminal extension / Telomerase ribonucleoprotein complex - RNA binding domain / Telomerase reverse transcriptase / Telomerase ribonucleoprotein complex - RNA-binding domain / Telomerase ribonucleoprotein complex - RNA binding domain / : / Histone H2B signature. / Histone H2A conserved site / Histone H2A signature. / Histone H2B / Histone H2B / Histone H2A, C-terminal domain / C-terminus of histone H2A / Histone 2A / Histone H2A / Reverse transcriptase domain / Reverse transcriptase (RNA-dependent DNA polymerase) / Reverse transcriptase (RT) catalytic domain profile. / Histone H2A/H2B/H3 / Core histone H2A/H2B/H3/H4 domain / Histone-fold / DNA/RNA polymerase superfamily
Similarity search - Domain/homology
: / DNA / RNA / RNA (> 10) / RNA (> 100) / Histone H2A / Histone H2B / Telomerase reverse transcriptase / Adrenocortical dysplasia protein homolog
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.8 Å
AuthorsBalch, S. / Sekne, Z. / Franco-Echevarria, E. / Ludzia, P. / Kretsch, R.C. / Sun, W. / Yu, H. / Ghanim, G.E. / Sigurdur, T.R. / Ding, Y. ...Balch, S. / Sekne, Z. / Franco-Echevarria, E. / Ludzia, P. / Kretsch, R.C. / Sun, W. / Yu, H. / Ghanim, G.E. / Sigurdur, T.R. / Ding, Y. / Das, R. / Nguyen, T.H.D.
Funding support United Kingdom, United States, European Union, China, 8items
OrganizationGrant numberCountry
UK Research and Innovation (UKRI)MC_UP_1201/19 United Kingdom
Jane Coffin Childs (JCC) Fund United States
European Molecular Biology Organization (EMBO)European Union
Wellcome Trust226015/Z/22/Z United Kingdom
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)2R35GM122579 United States
Howard Hughes Medical Institute (HHMI) United States
Chinese Scholarship Council202206620047 China
Biotechnology and Biological Sciences Research Council (BBSRC)BB/X01102X/1 United Kingdom
CitationJournal: Science / Year: 2025
Title: Cryo-EM structure of human telomerase dimer reveals H/ACA RNP-mediated dimerization.
Authors: Sebastian Balch / Zala Sekne / Elsa Franco-Echevarría / Patryk Ludzia / Rachael C Kretsch / Wenqing Sun / Haopeng Yu / George E Ghanim / Sigurdur Thorkelsson / Yiliang Ding / Rhiju Das / ...Authors: Sebastian Balch / Zala Sekne / Elsa Franco-Echevarría / Patryk Ludzia / Rachael C Kretsch / Wenqing Sun / Haopeng Yu / George E Ghanim / Sigurdur Thorkelsson / Yiliang Ding / Rhiju Das / Thi Hoang Duong Nguyen /
Abstract: Telomerase ribonucleoprotein (RNP) synthesizes telomeric repeats at chromosome ends using a telomerase reverse transcriptase (TERT) and a telomerase RNA (hTR in humans). Previous structural work ...Telomerase ribonucleoprotein (RNP) synthesizes telomeric repeats at chromosome ends using a telomerase reverse transcriptase (TERT) and a telomerase RNA (hTR in humans). Previous structural work showed that human telomerase is typically monomeric, containing a single copy of TERT and hTR. Evidence for dimeric complexes exists, although the composition, high-resolution structure, and function remain elusive. Here, we report the cryo-electron microscopy (cryo-EM) structure of a human telomerase dimer bound to telomeric DNA. The structure reveals a 26-subunit assembly and a dimerization interface mediated by the Hinge and ACA box (H/ACA) RNP of telomerase. Premature aging disease mutations map to this interface. Disrupting dimer formation affects RNP assembly, bulk telomerase activity, and telomere maintenance in cells. Our findings address a long-standing enigma surrounding the telomerase dimer and suggest a role for the dimer in telomerase assembly.
History
DepositionFeb 28, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 16, 2025Provider: repository / Type: Initial release
Revision 1.1Jul 23, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.name / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Telomerase reverse transcriptase
B: hTR, human telomerase RNA (253-mer)
L: Histone H2A
M: Histone H2B
N: DNA (5'-D(P*GP*TP*TP*AP*GP*GP*G)-3')
O: Adrenocortical dysplasia protein homolog


Theoretical massNumber of molelcules
Total (without water)356,0966
Polymers356,0966
Non-polymers00
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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Protein , 4 types, 4 molecules ALMO

#1: Protein Telomerase reverse transcriptase / HEST2 / Telomerase catalytic subunit / Telomerase-associated protein 2 / TP2


Mass: 127195.812 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TERT, EST2, TCS1, TRT / Plasmid: pcDNA3.1 / Cell line (production host): 293T / Organ (production host): Kidney / Production host: Homo sapiens (human) / References: UniProt: O14746, RNA-directed DNA polymerase
#3: Protein Histone H2A


Mass: 14140.584 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Cell line: 293T / Organ: Kidney / Plasmid details: Endogenous / References: UniProt: B2R5B3
#4: Protein Histone H2B


Mass: 18074.932 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Cell line: 293T / Organ: Kidney / Plasmid details: Endogenous / References: UniProt: B4DR52
#6: Protein Adrenocortical dysplasia protein homolog / POT1 and TIN2-interacting protein


Mass: 49013.086 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ACD, PIP1, PTOP, TINT1, TPP1 / Cell line (production host): Sf9 / Production host: Spodoptera (butterflies/moths) / References: UniProt: Q96AP0

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RNA chain / DNA chain , 2 types, 2 molecules BN

#2: RNA chain hTR, human telomerase RNA (253-mer)


Mass: 145477.797 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Plasmid: pcDNA3.1 / Cell line (production host): 293T / Organ (production host): Kidney / Production host: Homo sapiens (human) / References: GenBank: 1932797
#5: DNA chain DNA (5'-D(P*GP*TP*TP*AP*GP*GP*G)-3')


Mass: 2193.458 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)

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Details

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: Catalytic core 1 of dimeric human telomerase / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
Buffer component
IDConc.NameFormulaBuffer-ID
120.0 mMHEPESC8H18N2O4S1
2150.0 mMSodium ChlorideNaCl1
32.0 mMMagnesium ChlorideMgCl21
40.05 %Igepal CA630(C2H4O)nC14H22O1
51.0 %TrehaloseC12H22O111
61.0 mMDTTC4H10O2S21
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 400 divisions/in. / Grid type: C-flat
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: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 81000 X / Calibrated magnification: 45872 X / Nominal defocus max: 2400 nm / Nominal defocus min: 1000 nm / Cs: 2.7 mm / C2 aperture diameter: 50 µm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Temperature (min): 78 K
Image recordingAverage exposure time: 2.5 sec. / Electron dose: 48 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 4 / Num. of real images: 66992
EM imaging opticsEnergyfilter name: GIF Quantum LS / Energyfilter slit width: 20 eV

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Processing

EM software
IDNameVersionCategory
1RELION4particle selection
2EPU2.13.0.3175RELimage acquisition
4CTFFIND4CTF correction
7Coot0.9.8.1model fitting
8UCSF ChimeraX1.5model fitting
10RELION4initial Euler assignment
11RELION5final Euler assignment
12RELION5classification
13RELION53D reconstruction
14REFMAC5.8model refinement
15Servalcat0.4.70model refinement
Image processingDetails: All images were processed using RELION 4.0, RELION 5.0 and CryoSPARC 4.1.2
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 1871285
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 138966 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT / Space: RECIPROCAL
Atomic model buildingPDB-ID: 7QXA

7qxa


Accession code: 7QXA / Source name: PDB / Type: experimental model
RefinementResolution: 3.8→173.68 Å / Cor.coef. Fo:Fc: 0.958 / SU B: 36.58 / SU ML: 0.508 / ESU R: 0.637
Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES
Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
RfactorNum. reflection% reflection
Rwork0.35425 --
obs0.35425 130993 100 %
Solvent computationSolvent model: PARAMETERS FOR MASK CACLULATION
Displacement parametersBiso mean: 318.778 Å2
Refinement stepCycle: 1 / Total: 15471
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
ELECTRON MICROSCOPYr_bond_refined_d0.0480.01216462
ELECTRON MICROSCOPYr_bond_other_d0.0010.01712586
ELECTRON MICROSCOPYr_angle_refined_deg1.3411.8523346
ELECTRON MICROSCOPYr_angle_other_deg0.6371.7429134
ELECTRON MICROSCOPYr_dihedral_angle_1_deg9.247.6612568
ELECTRON MICROSCOPYr_dihedral_angle_2_deg3.4625126
ELECTRON MICROSCOPYr_dihedral_angle_3_deg12.137101766
ELECTRON MICROSCOPYr_dihedral_angle_4_deg
ELECTRON MICROSCOPYr_chiral_restr0.090.2072911
ELECTRON MICROSCOPYr_gen_planes_refined0.0070.0215235
ELECTRON MICROSCOPYr_gen_planes_other0.0030.023538
ELECTRON MICROSCOPYr_nbd_refined
ELECTRON MICROSCOPYr_nbd_other
ELECTRON MICROSCOPYr_nbtor_refined
ELECTRON MICROSCOPYr_nbtor_other
ELECTRON MICROSCOPYr_xyhbond_nbd_refined
ELECTRON MICROSCOPYr_xyhbond_nbd_other
ELECTRON MICROSCOPYr_metal_ion_refined
ELECTRON MICROSCOPYr_metal_ion_other
ELECTRON MICROSCOPYr_symmetry_vdw_refined
ELECTRON MICROSCOPYr_symmetry_vdw_other
ELECTRON MICROSCOPYr_symmetry_hbond_refined
ELECTRON MICROSCOPYr_symmetry_hbond_other
ELECTRON MICROSCOPYr_symmetry_metal_ion_refined
ELECTRON MICROSCOPYr_symmetry_metal_ion_other
ELECTRON MICROSCOPYr_mcbond_it30.17530.844978
ELECTRON MICROSCOPYr_mcbond_other30.17330.844978
ELECTRON MICROSCOPYr_mcangle_it49.5955.5466205
ELECTRON MICROSCOPYr_mcangle_other49.58655.5536206
ELECTRON MICROSCOPYr_scbond_it31.54733.50111484
ELECTRON MICROSCOPYr_scbond_other31.54533.50411485
ELECTRON MICROSCOPYr_scangle_it
ELECTRON MICROSCOPYr_scangle_other51.80760.9517142
ELECTRON MICROSCOPYr_long_range_B_refined90.684446.9483627
ELECTRON MICROSCOPYr_long_range_B_other90.684446.9483628
ELECTRON MICROSCOPYr_rigid_bond_restr
ELECTRON MICROSCOPYr_sphericity_free
ELECTRON MICROSCOPYr_sphericity_bonded
LS refinement shellResolution: 3.8→3.899 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0 0 -
Rwork1.523 9819 -
obs--100 %

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