PuSH - Publikationsserver des Helmholtz Zentrums München

Oberheide, A.* ; van den Oetelaar, M.C.M.* ; Scheele, J.J.A.* ; Borggräfe, J. ; Engelen, S.F.H.* ; Sattler, M. ; Ottmann, C.* ; Cossar, P.J.* ; Brunsveld, L.*

Site-specific molecular glues for the 14-3-3/Tau pS214 protein-protein interaction via reversible covalent imine tethering.

RSC Med. Chem., DOI: 10.1039/d4md00833b (2025)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
Protein-protein interactions (PPIs) are key regulators of various cellular processes. Modulating PPIs with small molecules has gained increasing attention in drug discovery, particularly targeting the 14-3-3 protein family, which interacts with several hundred client proteins and plays a central role in cellular networks. However, targeting a specific PPI of the hub protein 14-3-3, with its plethora of potential client proteins, poses a significant selectivity challenge. This not only involves the selectivity of 14-3-3 PPIs with other client proteins, but also the selective stabilization of a specific 14-3-3 binding site within a protein partner featuring several binding sites. The interaction of 14-3-3 with Tau, characterized by different phospho-site driven binding modes, forms a valuable, disease-relevant, 14-3-3 multivalent model PPI to explore this selectivity issue. This work presents the identification and early-stage optimization of small molecule fragment-like stabilizers for a specific binding site of the 14-3-3/Tau PPI. Using different biophysical assays, the stabilizing potency of the imine-bond forming molecules was mapped and X-ray crystallography studies provided structural data on the binding mode of the ternary complexes. Exploiting the unique topologies and functionalities of the different binding sites enabled the engineering of selectivity for this initial molecular glue matter for the pS214 binding site, over a second 14-3-3 binding site in Tau (pS324). These reversible covalent tool compounds will allow for the further exploration of the role of 14-3-3 in Tau aggregation.
Altmetric
Weitere Metriken?
[➜Einloggen]
Zusatzinfos bearbeiten [➜Einloggen]
Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Tau-protein; Drug Discovery; Phosphorylation
ISSN (print) / ISBN 2632-8682
e-ISSN 2632-8682
Zeitschrift RSC Medicinal Chemistry
Verlag Royal Society of Chemistry (RSC)
Verlagsort Thomas Graham House, Science Park, Milton Rd, Cambridge Cb4 0wf, Cambs, England
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Structural Biology (STB)
Förderungen European Union through ERC
Dutch Research Council NWO
European Union
Horizon 2020