Upon binding, ligands can chaperone their protein targets by preventing them from misfolding and aggregating. Thus, an organic molecule that works as folding chaperone for a protein might be its specific ligand, and, similarly, the chaperone potential could represent an alternative readout in a molecular screening campaign toward the identification of new hits. Here we show that small molecules selected for acting as pharmacological chaperones on a misfolded mutant of the Frizzled4 (Fz4) receptor bind and modulate wild-type Fz4, representing what are to our knowledge the first organic ligands of this until-now-undruggable GPCR. The novelty and the advantages of the screening platform, the allosteric binding site addressed by these new ligands and the mechanism they use to modulate Fz4 suggest new avenues for development of inhibitors of the Wnt–b-catenin pathway and for drug discovery.

Pharmacological folding chaperones act as allosteric ligands of Frizzled4 / Generoso, S. F; Giustiniano, M; LA REGINA, Giuseppe; Bottone, S; Passacantilli, Sara; Di Maro, S; Cassese, H; Bruno, A; Mallardo, M; Dentice, M; Silvestri, Romano; Marinelli, L; Sarnataro, D; Bonatti, S; Novellino, E; Stornaiuolo, M.. - In: NATURE CHEMICAL BIOLOGY. - ISSN 1552-4450. - STAMPA. - 11:4(2015), pp. 280-286. [10.1038/nchembio.1770]

Pharmacological folding chaperones act as allosteric ligands of Frizzled4

LA REGINA, GIUSEPPE;PASSACANTILLI, SARA;SILVESTRI, Romano;
2015

Abstract

Upon binding, ligands can chaperone their protein targets by preventing them from misfolding and aggregating. Thus, an organic molecule that works as folding chaperone for a protein might be its specific ligand, and, similarly, the chaperone potential could represent an alternative readout in a molecular screening campaign toward the identification of new hits. Here we show that small molecules selected for acting as pharmacological chaperones on a misfolded mutant of the Frizzled4 (Fz4) receptor bind and modulate wild-type Fz4, representing what are to our knowledge the first organic ligands of this until-now-undruggable GPCR. The novelty and the advantages of the screening platform, the allosteric binding site addressed by these new ligands and the mechanism they use to modulate Fz4 suggest new avenues for development of inhibitors of the Wnt–b-catenin pathway and for drug discovery.
2015
ephrogenic diabetes-insipidus; cell-surface expression; dishevelled dep domain; mass-spectrometry data; endoplasmic-reticulum; structural basis; drosophila-melanogaster; colorectal-cancer; signaling pathway; receptor mutants
01 Pubblicazione su rivista::01a Articolo in rivista
Pharmacological folding chaperones act as allosteric ligands of Frizzled4 / Generoso, S. F; Giustiniano, M; LA REGINA, Giuseppe; Bottone, S; Passacantilli, Sara; Di Maro, S; Cassese, H; Bruno, A; Mallardo, M; Dentice, M; Silvestri, Romano; Marinelli, L; Sarnataro, D; Bonatti, S; Novellino, E; Stornaiuolo, M.. - In: NATURE CHEMICAL BIOLOGY. - ISSN 1552-4450. - STAMPA. - 11:4(2015), pp. 280-286. [10.1038/nchembio.1770]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/764098
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