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- PDB-9shy: Cryo-EM structure of the catalytic core of human telomerase at th... -

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Basic information

Entry
Database: PDB / ID: 9shy
TitleCryo-EM structure of the catalytic core of human telomerase at the initiation state of the repeat addition cycle
Components
  • Adrenocortical dysplasia protein homolog
  • DNA (5'-D(P*TP*TP*AP*GP*GP*GP*TP*TP*AP*G)-3')
  • Histone H2A
  • Histone H2B
  • Telomerase reverse transcriptase
  • hTR, human telomerase RNA
KeywordsRNA BINDING PROTEIN / telomerase / H/ACA
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 / RNA-templated DNA biosynthetic process / establishment of protein localization to telomere / telomerase inhibitor activity / 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 / Polymerase switching on the C-strand of the telomere / telomerase RNA binding / embryonic limb morphogenesis / Processive synthesis on the C-strand of the telomere / 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 repeat DNA binding / negative regulation of telomere maintenance via telomerase / positive regulation of telomere maintenance / negative regulation of cellular senescence / mitochondrial nucleoid / replicative senescence / Telomere Extension By Telomerase / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / response to cadmium ion / positive regulation of G1/S transition of mitotic cell cycle / negative regulation of endothelial cell apoptotic process / positive regulation of Wnt signaling pathway / 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 / positive regulation of D-glucose import across plasma membrane / skeletal system development / mitochondrion organization / intracellular protein transport / regulation of protein stability / Formation of the beta-catenin:TCF transactivating complex / PML body / positive regulation of miRNA transcription / RNA-directed DNA polymerase / DNA Damage/Telomere Stress Induced Senescence / transcription coactivator binding / RNA-directed DNA polymerase activity / positive regulation of angiogenesis / protein import into nucleus / 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 H2A conserved site / Histone H2A signature. / Histone H2B signature. / Histone H2B / Histone H2B / Histone H2A, C-terminal domain / C-terminus of histone H2A / Histone 2A / Histone H2A / Reverse transcriptase domain / 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
Chem-1GC / : / DNA / DNA (> 10) / 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: 3.53 Å
AuthorsBalch, S. / Franco-Echevarria, E. / Ghanim, G.E. / Kretsch, R.C. / Das, R. / Nguyen, T.H.D.
Funding support United Kingdom, European Union, United States, 5items
OrganizationGrant numberCountry
UK Research and Innovation (UKRI)MC_UP_1201/19 United Kingdom
European Molecular Biology Organization (EMBO)Young Investigator Program AwardEuropean 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
CitationJournal: Nat Commun / Year: 2026
Title: Structures of nucleotide-bound human telomerase at several steps of its telomeric DNA repeat addition cycle.
Authors: Sebastian Balch / Elsa Franco-Echevarría / George E Ghanim / Rachael C Kretsch / Rhiju Das / Thi Hoang Duong Nguyen /
Abstract: In most eukaryotes, the reverse transcriptase telomerase counteracts telomere shortening by processively adding telomeric DNA repeat sequences to chromosome ends. Telomerase activity depends on the ...In most eukaryotes, the reverse transcriptase telomerase counteracts telomere shortening by processively adding telomeric DNA repeat sequences to chromosome ends. Telomerase activity depends on the telomerase reverse transcriptase (TERT) and the telomerase RNA (hTR in humans). Processive telomere elongation is critical for genome stability, and defects in this mechanism are linked to cellular dysfunction and human disease. However, the structural basis for telomerase repeat addition processivity in humans has remained elusive. Here, we present cryo-electron microscopy structures of human telomerase bound to telomeric DNA and an incoming nucleotide, captured at three distinct stages of its repeat addition cycle: initiation, elongation, and pre-termination. Across these states, the TERT active site maintains a conserved architecture that stabilises a short DNA-RNA duplex of constant length of four base-pairs. Beyond the active site, we identify dynamic structural features in both TERT and hTR that facilitate substrate engagement and RNA template repositioning, thereby supporting the synthesis of successive telomeric repeats. Together, these structures provide key insights into how human telomerase achieves its unique processivity to maintain telomere length and genome integrity.
History
DepositionAug 28, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 28, 2026Provider: repository / Type: Initial release
Revision 1.0Jan 28, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jan 28, 2026Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Jan 28, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jan 28, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jan 28, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jan 28, 2026Data content type: Mask / Part number: 1 / Data content type: Mask / Provider: repository / Type: Initial release
Revision 1.0Jan 28, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)365,1597
Polymers364,6546
Non-polymers5051
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
#2: 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 / References: UniProt: B2R5B3
#3: 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 / References: UniProt: B4DR52
#5: Protein Adrenocortical dysplasia protein homolog / POT1 and TIN2-interacting protein


Mass: 49013.086 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Cell line: 293T / References: UniProt: Q96AP0

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DNA chain / RNA chain / Non-polymers , 3 types, 3 molecules NB

#4: DNA chain DNA (5'-D(P*TP*TP*AP*GP*GP*GP*TP*TP*AP*G)-3')


Mass: 10751.889 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)
#6: RNA chain hTR, human telomerase RNA


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 / Production host: Homo sapiens (human) / References: GenBank: 1932797
#7: Chemical ChemComp-1GC / 2'-deoxy-5'-O-[(R)-hydroxy{[(S)-hydroxy(phosphonooxy)phosphoryl]methyl}phosphoryl]guanosine


Mass: 505.208 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H18N5O12P3 / 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: Cryo-EM structure of the catalytic core of human telomerase at the initiation state of the repeat addition cycle
Type: COMPLEX / Entity ID: #1-#6 / Source: RECOMBINANT
Molecular weightValue: 0.311 MDa / Experimental 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: TFS 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 real images: 61257
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
10REFMAC5.8model refinement
11Servalcat0.4.70model refinement
12RELION4initial Euler assignment
13RELION5final Euler assignment
14RELION5classification
15RELION53D reconstruction
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: 8092334
3D reconstructionResolution: 3.53 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 105598 / Symmetry type: POINT
Atomic model buildingPDB-ID: 7QXA

7qxa


Accession code: 7QXA / Source name: PDB / Type: experimental model
RefinementResolution: 3.53→173.68 Å / Cor.coef. Fo:Fc: 0.959 / SU B: 28.109 / SU ML: 0.426 / ESU R: 0.485
Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES
Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
RfactorNum. reflection% reflection
Rwork0.34113 --
obs0.34113 158057 100 %
Solvent computationSolvent model: PARAMETERS FOR MASK CACLULATION
Displacement parametersBiso mean: 249.571 Å2
Refinement stepCycle: 1 / Total: 15563
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
ELECTRON MICROSCOPYr_bond_refined_d0.0110.01216562
ELECTRON MICROSCOPYr_bond_other_d00.01712630
ELECTRON MICROSCOPYr_angle_refined_deg1.5381.84623503
ELECTRON MICROSCOPYr_angle_other_deg0.661.73929243
ELECTRON MICROSCOPYr_dihedral_angle_1_deg8.7117.6482577
ELECTRON MICROSCOPYr_dihedral_angle_2_deg5.695126
ELECTRON MICROSCOPYr_dihedral_angle_3_deg11.377101766
ELECTRON MICROSCOPYr_dihedral_angle_4_deg
ELECTRON MICROSCOPYr_chiral_restr0.1240.2082939
ELECTRON MICROSCOPYr_gen_planes_refined0.0080.0215288
ELECTRON MICROSCOPYr_gen_planes_other0.0050.023550
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_it14.9221.1364978
ELECTRON MICROSCOPYr_mcbond_other14.91921.1364978
ELECTRON MICROSCOPYr_mcangle_it23.62838.0616205
ELECTRON MICROSCOPYr_mcangle_other23.62638.0616206
ELECTRON MICROSCOPYr_scbond_it14.20628.98211584
ELECTRON MICROSCOPYr_scbond_other14.18728.98611575
ELECTRON MICROSCOPYr_scangle_it
ELECTRON MICROSCOPYr_scangle_other22.76252.81117299
ELECTRON MICROSCOPYr_long_range_B_refined40.185393.2685961
ELECTRON MICROSCOPYr_long_range_B_other40.184393.2585962
ELECTRON MICROSCOPYr_rigid_bond_restr
ELECTRON MICROSCOPYr_sphericity_free
ELECTRON MICROSCOPYr_sphericity_bonded
LS refinement shellResolution: 3.53→3.622 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0 0 -
Rwork0.561 11736 -
obs--100 %

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