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  1. Article: The resting state of the human T-cell receptor-CD3 complex.

    Notti, Ryan Q / Yi, Fei / Heissel, Søren / Bush, Martin W / Molina, Henrik / Molvi, Zaki / Klebanoff, Christopher A / Walz, Thomas

    bioRxiv : the preprint server for biology

    2024  

    Abstract: The T-cell receptor (TCR) is central to the ligand-dependent activation of T lymphocytes and as such orchestrates both adaptive and pathologic immune ... ...

    Abstract The T-cell receptor (TCR) is central to the ligand-dependent activation of T lymphocytes and as such orchestrates both adaptive and pathologic immune processes
    Language English
    Publishing date 2024-04-08
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.08.22.554360
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Shelterin is a dimeric complex with extensive structural heterogeneity.

    Zinder, John C / Olinares, Paul Dominic B / Svetlov, Vladimir / Bush, Martin W / Nudler, Evgeny / Chait, Brian T / Walz, Thomas / de Lange, Titia

    Proceedings of the National Academy of Sciences of the United States of America

    2022  Volume 119, Issue 31, Page(s) e2201662119

    Abstract: Human shelterin is a six-subunit complex-composed of TRF1, TRF2, Rap1, TIN2, TPP1, and POT1-that binds telomeres, protects them from the DNA-damage response, and regulates the maintenance of telomeric DNA. Although high-resolution structures have been ... ...

    Abstract Human shelterin is a six-subunit complex-composed of TRF1, TRF2, Rap1, TIN2, TPP1, and POT1-that binds telomeres, protects them from the DNA-damage response, and regulates the maintenance of telomeric DNA. Although high-resolution structures have been generated of the individual structured domains within shelterin, the architecture and stoichiometry of the full complex are currently unknown. Here, we report the purification of shelterin subcomplexes and reconstitution of the entire complex using full-length, recombinant subunits. By combining negative-stain electron microscopy (EM), cross-linking mass spectrometry (XLMS), AlphaFold modeling, mass photometry, and native mass spectrometry (MS), we obtain stoichiometries as well as domain-scale architectures of shelterin subcomplexes and determine that they feature extensive conformational heterogeneity. For POT1/TPP1 and POT1/TPP1/TIN2, we observe high variability in the positioning of the POT1 DNA-binding domain, the TPP1 oligonucleotide/oligosaccharide-binding (OB) fold, and the TIN2 TRFH domain with respect to the C-terminal domains of POT1. Truncation of unstructured linker regions in TIN2, TPP1, and POT1 did not reduce the conformational variability of the heterotrimer. Shelterin and TRF1-containing subcomplexes form fully dimeric stoichiometries, even in the absence of DNA substrates. Shelterin and its subcomplexes showed extensive conformational variability, regardless of the presence of DNA substrates. We conclude that shelterin adopts a multitude of conformations and argue that its unusual architectural variability is beneficial for its many functions at telomeres.
    MeSH term(s) Humans ; Mass Spectrometry ; Microscopy, Electron ; Protein Domains ; Shelterin Complex/chemistry
    Chemical Substances Shelterin Complex
    Language English
    Publishing date 2022-07-26
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.2201662119
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1148: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
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  3. Article ; Online: Cryo-EM structure of the human CST-Polα/primase complex in a recruitment state.

    Cai, Sarah W / Zinder, John C / Svetlov, Vladimir / Bush, Martin W / Nudler, Evgeny / Walz, Thomas / de Lange, Titia

    Nature structural & molecular biology

    2022  Volume 29, Issue 8, Page(s) 813–819

    Abstract: The CST-Polα/primase complex is essential for telomere maintenance and functions to counteract resection at double-strand breaks. We report a 4.6-Å resolution cryo-EM structure of human CST-Polα/primase, captured prior to catalysis in a recruitment state ...

    Abstract The CST-Polα/primase complex is essential for telomere maintenance and functions to counteract resection at double-strand breaks. We report a 4.6-Å resolution cryo-EM structure of human CST-Polα/primase, captured prior to catalysis in a recruitment state stabilized by chemical cross-linking. Our structure reveals an evolutionarily conserved interaction between the C-terminal domain of the catalytic POLA1 subunit and an N-terminal expansion in metazoan CTC1. Cross-linking mass spectrometry and negative-stain EM analysis provide insight into CST binding by the flexible POLA1 N-terminus. Finally, Coats plus syndrome disease mutations previously characterized to disrupt formation of the CST-Polα/primase complex map to protein-protein interfaces observed in the recruitment state. Together, our results shed light on the architecture and stoichiometry of the metazoan fill-in machinery.
    MeSH term(s) Animals ; Cryoelectron Microscopy ; DNA Primase/genetics ; DNA Primase/metabolism ; Humans ; Shelterin Complex ; Telomere/metabolism ; Telomere-Binding Proteins/metabolism
    Chemical Substances Shelterin Complex ; Telomere-Binding Proteins ; DNA Primase (EC 2.7.7.-)
    Language English
    Publishing date 2022-05-16
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2126708-X
    ISSN 1545-9985 ; 1545-9993
    ISSN (online) 1545-9985
    ISSN 1545-9993
    DOI 10.1038/s41594-022-00766-y
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 4101: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)
    Zs.MG 56: Show issues

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  4. Article ; Online: Structural and kinetic basis for the selectivity of aducanumab for aggregated forms of amyloid-β.

    Arndt, Joseph W / Qian, Fang / Smith, Benjamin A / Quan, Chao / Kilambi, Krishna Praneeth / Bush, Martin W / Walz, Thomas / Pepinsky, R Blake / Bussière, Thierry / Hamann, Stefan / Cameron, Thomas O / Weinreb, Paul H

    Scientific reports

    2018  Volume 8, Issue 1, Page(s) 6412

    Abstract: Aducanumab, a human-derived antibody targeting amyloid-β (Aβ), is in Phase 3 clinical trials for the treatment of Alzheimer's disease. Biochemical and structural analyses show that aducanumab binds a linear epitope formed by amino acids 3-7 of the Aβ ... ...

    Abstract Aducanumab, a human-derived antibody targeting amyloid-β (Aβ), is in Phase 3 clinical trials for the treatment of Alzheimer's disease. Biochemical and structural analyses show that aducanumab binds a linear epitope formed by amino acids 3-7 of the Aβ peptide. Aducanumab discriminates between monomers and oligomeric or fibrillar aggregates based on weak monovalent affinity, fast binding kinetics and strong avidity for epitope-rich aggregates. Direct comparative studies with analogs of gantenerumab, bapineuzumab and solanezumab demonstrate clear differentiation in the binding properties of these antibodies. The crystal structure of the Fab fragment of aducanumab bound to its epitope peptide reveals that aducanumab binds to the N terminus of Aβ in an extended conformation, distinct from those seen in structures with other antibodies that target this immunodominant epitope. Aducanumab recognizes a compact epitope that sits in a shallow pocket on the antibody surface. In silico analyses suggest that aducanumab interacts weakly with the Aβ monomer and may accommodate a variety of peptide conformations, further supporting its selectivity for Aβ aggregates. Our studies provide a structural rationale for the low affinity of aducanumab for non-pathogenic monomers and its greater selectivity for aggregated forms than is seen for other Aβ-targeting antibodies.
    MeSH term(s) Alzheimer Disease/therapy ; Amyloid beta-Peptides/immunology ; Amyloid beta-Peptides/metabolism ; Antibodies, Monoclonal, Humanized/chemistry ; Antibodies, Monoclonal, Humanized/immunology ; Antibodies, Monoclonal, Humanized/metabolism ; Antibodies, Monoclonal, Humanized/therapeutic use ; Binding Sites, Antibody ; Enzyme-Linked Immunosorbent Assay ; Humans ; Immunotherapy ; Kinetics ; Molecular Docking Simulation ; Protein Conformation ; Surface Plasmon Resonance
    Chemical Substances Amyloid beta-Peptides ; Antibodies, Monoclonal, Humanized ; aducanumab (105J35OE21)
    Language English
    Publishing date 2018-04-23
    Publishing country England
    Document type Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-018-24501-0
    Database MEDical Literature Analysis and Retrieval System OnLINE

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