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- PDB-9q14: Human telomerase catalytic core with shelterin protein TPP1, BIBR... -

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Basic information

Entry
Database: PDB / ID: 9q14
TitleHuman telomerase catalytic core with shelterin protein TPP1, BIBR1532 and DNA primer ending in TTAG
Components
  • Adrenocortical dysplasia protein homolog
  • Histone H2A.J
  • Histone H2B type 1-C/E/F/G/I
  • Telomerase RNA
  • Telomerase reverse transcriptase
  • Telomeric repeat substrate
KeywordsRNA BINDING PROTEIN/RNA/DNA / DNA polymerase / Reverse Transcriptase / Ribonucleoprotein / RNA BINDING PROTEIN / RNA BINDING PROTEIN-RNA-DNA complex
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 / siRNA transcription / positive regulation of protein localization to nucleolus / telomerase catalytic core complex ...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 / siRNA transcription / positive regulation of protein localization to nucleolus / telomerase catalytic core complex / protection from non-homologous end joining at telomere / establishment of protein localization to telomere / RNA-templated DNA biosynthetic process / regulation of establishment of protein localization to telomere / telomerase activity / telomerase inhibitor activity / shelterin complex / Telomere C-strand synthesis initiation / siRNA processing / Regulation of MITF-M-dependent genes involved in DNA replication, damage repair and senescence / Telomere C-strand (Lagging Strand) Synthesis / positive regulation of stem cell proliferation / nuclear telomere cap complex / telomere capping / telomere maintenance via recombination / Polymerase switching on the C-strand of the telomere / positive regulation of vascular associated smooth muscle cell migration / telomerase holoenzyme complex / telomerase RNA binding / Processive synthesis on the C-strand of the telomere / negative regulation of cellular senescence / Removal of the Flap Intermediate from the C-strand / DNA biosynthetic process / protein localization to chromosome, telomeric region / telomeric repeat DNA binding / RNA-templated transcription / negative regulation of telomere maintenance via telomerase / negative regulation of endothelial cell apoptotic process / positive regulation of telomere maintenance / replicative senescence / response to cadmium ion / mitochondrial nucleoid / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / Telomere Extension By Telomerase / positive regulation of Wnt signaling pathway / telomere maintenance via telomerase / positive regulation of vascular associated smooth muscle cell proliferation / positive regulation of G1/S transition of mitotic cell cycle / DNA polymerase binding / Replacement of protamines by nucleosomes in the male pronucleus / Packaging Of Telomere Ends / Recognition and association of DNA glycosylase with site containing an affected purine / Cleavage of the damaged purine / ChAHP complex assembly / telomere maintenance / Deposition of new CENPA-containing nucleosomes at the centromere / Recognition and association of DNA glycosylase with site containing an affected pyrimidine / Cleavage of the damaged pyrimidine / protein import into nucleus / RNA Polymerase I Promoter Opening / Inhibition of DNA recombination at telomere / Assembly of the ORC complex at the origin of replication / FXIIa activates plasma kallikrein-kinin system / Regulation of endogenous retroelements by the Human Silencing Hub (HUSH) complex / Meiotic synapsis / DNA polymerase activity / DNA methylation / Condensation of Prophase Chromosomes / Chromatin modifications during the maternal to zygotic transition (MZT) / HCMV Late Events / SIRT1 negatively regulates rRNA expression / mitochondrion organization / NuRD complex assembly / ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression / Interaction of NuRD complexes with transcription factors / PRC2 methylates histones and DNA / Regulation of endogenous retroelements by KRAB-ZFP proteins / regulation of protein stability / Defective pyroptosis / CHD1 and CHD2 subfamily / HDACs deacetylate histones / intracellular protein transport / CHD6, CHD7, CHD8, CHD9 subfamily / Transcriptional regulation by small RNAs / Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs) / RNA Polymerase I Promoter Escape / Nonhomologous End-Joining (NHEJ) / Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 / RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function / PML body / positive regulation of miRNA transcription / RNA-directed DNA polymerase / Negative Regulation of CDH1 Gene Transcription / NoRC negatively regulates rRNA expression / G2/M DNA damage checkpoint / Formation of the beta-catenin:TCF transactivating complex / B-WICH complex positively regulates rRNA expression / DNA Damage/Telomere Stress Induced Senescence / RNA-directed DNA polymerase activity / Meiotic recombination
Similarity search - Function
Adrenocortical dysplasia protein / : / Telomerase reverse transcriptase, C-terminal extension / Shelterin complex subunit TPP1/Est3 / Shelterin complex subunit, TPP1/ACD / Telomerase ribonucleoprotein complex - RNA binding domain / Telomerase reverse transcriptase / Telomerase ribonucleoprotein complex - RNA-binding domain / Telomerase ribonucleoprotein complex - RNA binding domain / : ...Adrenocortical dysplasia protein / : / Telomerase reverse transcriptase, C-terminal extension / Shelterin complex subunit TPP1/Est3 / Shelterin complex subunit, TPP1/ACD / 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-55C / : / DNA / DNA (> 10) / RNA / RNA (> 10) / RNA (> 100) / Telomerase reverse transcriptase / Histone H2B type 1-C/E/F/G/I / Adrenocortical dysplasia protein homolog / Histone H2A.J
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3 Å
AuthorsWang, Y. / Liu, B. / He, Y. / Feigon, J.
Funding support United States, 2items
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
CitationJournal: Nat Chem Biol / Year: 2026
Title: Structures of human telomerase with BIBR1532 reveal novel mechanism of inhibition.
Authors: Yuqing Wang / Baocheng Liu / Yao He / Juli Feigon /
Abstract: Human telomerase processively adds telomeric repeats (dGGTTAG) to chromosome 3'-ends to maintain telomere length. While mostly absent in somatic cells, telomerase is aberrantly upregulated in most ...Human telomerase processively adds telomeric repeats (dGGTTAG) to chromosome 3'-ends to maintain telomere length. While mostly absent in somatic cells, telomerase is aberrantly upregulated in most tumor cells to sustain cellular immortality, making it a promising oncology target. However, to date there are no reported structures of human telomerase with inhibitor, impeding structure-based drug design and optimization. We report nine cryo-electron microscopy structures of human telomerase with and without BIBR1532, a highly selective small-molecule telomerase inhibitor. Unexpectedly, BIBR1532 binds a previously unknown pocket between TERT finger and palm. BIBR1532 inhibits each step but disproportionately affects the rate-limiting first step of telomere repeat nucleotide addition. The structures reveal a rigid finger that explains telomerase's slow rate and low fidelity. Our study provides insights into telomerase catalytic mechanism and its inhibition by BIBR1532, explains why prior BIBR derivatives did not improve potency and suggests a rational approach for design of small-molecule telomerase inhibitors.
History
DepositionAug 13, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 17, 2026Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
C: Adrenocortical dysplasia protein homolog
F: Histone H2A.J
G: Histone H2B type 1-C/E/F/G/I
D: Telomeric repeat substrate
B: Telomerase RNA
A: Telomerase reverse transcriptase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)327,8617
Polymers327,5296
Non-polymers3311
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 , 4 types, 4 molecules CFGA

#1: Protein Adrenocortical dysplasia protein homolog / POT1 and TIN2-interacting protein


Mass: 17672.637 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 / Production host: Escherichia coli (E. coli) / References: UniProt: Q96AP0
#2: Protein Histone H2A.J / H2a/j


Mass: 14047.451 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: Q9BTM1
#3: Protein Histone H2B type 1-C/E/F/G/I / Histone H2B.1 A / Histone H2B.a / H2B/a / Histone H2B.g / H2B/g / Histone H2B.h / H2B/h / Histone ...Histone H2B.1 A / Histone H2B.a / H2B/a / Histone H2B.g / H2B/g / Histone H2B.h / H2B/h / Histone H2B.k / H2B/k / Histone H2B.l / H2B/l


Mass: 13937.213 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P62807
#6: Protein Telomerase reverse transcriptase / HEST2 / Telomerase catalytic subunit / Telomerase-associated protein 2 / TP2


Mass: 130711.492 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TERT, EST2, TCS1, TRT / Production host: Homo sapiens (human) / References: UniProt: O14746, RNA-directed DNA polymerase

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

#4: DNA chain Telomeric repeat substrate


Mass: 5682.672 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)
#5: RNA chain Telomerase RNA


Mass: 145477.797 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human) / References: GenBank: 1932797
#7: Chemical ChemComp-55C / 2-{[(2E)-3-(naphthalen-2-yl)but-2-enoyl]amino}benzoic acid / BIBR 1532


Mass: 331.365 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H17NO3 / 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

Component
IDNameTypeEntity IDParent-IDSource
1Human telomerase catalytic core with shelterin protein TPP1, BIBR1532 and DNA primer ending in TTAGCOMPLEX#1-#60MULTIPLE SOURCES
2Telomerase RNACOMPLEX#51RECOMBINANT
3Telomerase reverse transcriptaseCOMPLEX#61RECOMBINANT
4Adrenocortical dysplasia protein homologCOMPLEX#11RECOMBINANT
5DNA primerCOMPLEX#41SYNTHETIC
6Histones H2A and H2BCOMPLEX#2-#31NATURAL
Molecular weightExperimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
22Homo sapiens (human)9606
33Homo sapiens (human)9606
44Homo sapiens (human)9606
55Homo sapiens (human)9606
66Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
22Homo sapiens (human)9606
33Homo sapiens (human)9606
44Escherichia coli (E. coli)562
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE-PROPANE

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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 defocus max: 2500 nm / Nominal defocus min: 500 nm
Image recordingElectron dose: 45 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameCategory
1cryoSPARCparticle selection
2Topazparticle selection
14cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 394396 / Symmetry type: POINT
RefinementHighest resolution: 3 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00315481
ELECTRON MICROSCOPYf_angle_d0.54122000
ELECTRON MICROSCOPYf_dihedral_angle_d18.5937117
ELECTRON MICROSCOPYf_chiral_restr0.0352647
ELECTRON MICROSCOPYf_plane_restr0.0042023

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