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Binding of monovalent and bivalent ligands by transthyretin causes different short and long distance conformational changes

Corazza, A; Verona, G; Waudby, CA; Mangione, PP; Bingham, RP; Uings, I; Canetti, D; ... Bellotti, V; + view all (2019) Binding of monovalent and bivalent ligands by transthyretin causes different short and long distance conformational changes. Journal of Medicinal Chemistry , 62 (17) pp. 8274-8283. 10.1021/acs.jmedchem.9b01037. Green open access

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Abstract

The wild type protein, transthyretin (TTR), and over 120 genetic TTR variants are amyloidogenic and cause, respectively, sporadic and hereditary systemic TTR amyloidosis. The homotetrameric TTR contains two identical thyroxine binding pockets, occupation of which by specific ligands can inhibit TTR amyloidogenesis in vitro. Ligand binding stabilizes the tetramer, inhibiting its proteolytic cleavage and its dissociation. Here we show with solution-state NMR, that ligand binding induces long-distance conformational changes in the TTR that have not previously been detected by X-ray crystallography, consistently with the inhibition of the cleavage of the DE loop. The NMR findings, coupled with surface plasmon resonance measurements, have identified dynamic exchange processes underlying the negative cooperativity of binding of 'monovalent' ligand tafamidis. In contrast, mds84, our prototypic 'bivalent' ligand, which is a more potent stabilizer of TTR in vitro that occupies both thyroxine pockets and the intramolecular channel between them, has greater long distance effects.

Type: Article
Title: Binding of monovalent and bivalent ligands by transthyretin causes different short and long distance conformational changes
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1021/acs.jmedchem.9b01037
Publisher version: https://doi.org/10.1021/acs.jmedchem.9b01037
Language: English
Additional information: © 2019 American Chemical Society. This is an open access article published under a Creative Commons Attribution (CC-BY) License (https://pubs.acs.org/page/policy/authorchoice_ccby_termsofuse.html).
Keywords: Ligands, Cooperativity, Nuclear magnetic resonance spectroscopy, Screening assays, Conformational transitions
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Structural and Molecular Biology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inflammation
URI: https://discovery.ucl.ac.uk/id/eprint/10080147
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