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- EMDB-26091: Human telomerase catalytic core with TPP1-OB, P2a state 1-2 -

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Basic information

Entry
Database: EMDB / ID: EMD-26091
TitleHuman telomerase catalytic core with TPP1-OB, P2a state 1-2
Map dataTelomerase catalytic core with TPP1-OB, P2a state 1-2
Sample
  • Complex: human telomerase catalytic core with DNA-substrate
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.1 Å
AuthorsLiu B / He Y
Funding support United States, 3 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM131901 United States
National Science Foundation (NSF, United States)MCB2016540 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM071940 United States
CitationJournal: Nature / Year: 2022
Title: Structure of active human telomerase with telomere shelterin protein TPP1.
Authors: Baocheng Liu / Yao He / Yaqiang Wang / He Song / Z Hong Zhou / Juli Feigon /
Abstract: Human telomerase is a RNA-protein complex that extends the 3' end of linear chromosomes by synthesizing multiple copies of the telomeric repeat TTAGGG. Its activity is a determinant of cancer ...Human telomerase is a RNA-protein complex that extends the 3' end of linear chromosomes by synthesizing multiple copies of the telomeric repeat TTAGGG. Its activity is a determinant of cancer progression, stem cell renewal and cellular aging. Telomerase is recruited to telomeres and activated for telomere repeat synthesis by the telomere shelterin protein TPP1. Human telomerase has a bilobal structure with a catalytic core ribonuclear protein and a H and ACA box ribonuclear protein. Here we report cryo-electron microscopy structures of human telomerase catalytic core of telomerase reverse transcriptase (TERT) and telomerase RNA (TER (also known as hTR)), and of telomerase with the shelterin protein TPP1. TPP1 forms a structured interface with the TERT-unique telomerase essential N-terminal domain (TEN) and the telomerase RAP motif (TRAP) that are unique to TERT, and conformational dynamics of TEN-TRAP are damped upon TPP1 binding, defining the requirements for recruitment and activation. The structures further reveal that the elements of TERT and TER that are involved in template and telomeric DNA handling-including the TEN domain and the TRAP-thumb helix channel-are largely structurally homologous to those in Tetrahymena telomerase, and provide unique insights into the mechanism of telomerase activity. The binding site of the telomerase inhibitor BIBR1532 overlaps a critical interaction between the TER pseudoknot and the TERT thumb domain. Numerous mutations leading to telomeropathies are located at the TERT-TER and TEN-TRAP-TPP1 interfaces, highlighting the importance of TER-TERT and TPP1 interactions for telomerase activity, recruitment and as drug targets.
History
DepositionJan 28, 2022-
Header (metadata) releaseMay 4, 2022-
Map releaseMay 4, 2022-
UpdateMay 4, 2022-
Current statusMay 4, 2022Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_26091.png

Downloads & links

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Map

FileDownload / File: emd_26091.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationTelomerase catalytic core with TPP1-OB, P2a state 1-2
Voxel sizeX=Y=Z: 1.1 Å
Density
Contour LevelBy AUTHOR: 0.02
Minimum - Maximum-0.022015197 - 0.061628062
Average (Standard dev.)0.0002124855 (±0.0025431023)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 281.6 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : human telomerase catalytic core with DNA-substrate

EntireName: human telomerase catalytic core with DNA-substrate
Components
  • Complex: human telomerase catalytic core with DNA-substrate

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Supramolecule #1: human telomerase catalytic core with DNA-substrate

SupramoleculeName: human telomerase catalytic core with DNA-substrate / type: complex / Chimera: Yes / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Homo sapiens (human)

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 55.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: SPOT SCAN / Imaging mode: BRIGHT FIELD / Nominal defocus max: 4.0 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: EMDB MAP
EMDB ID:

7521

Final reconstructionResolution.type: BY AUTHOR / Resolution: 4.1 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 23715
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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