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Engineering selective competitors for the discrimination of highly conserved protein-protein interaction modules

Designing highly specific modulators of protein-protein interactions (PPIs) is especially challenging in the context of multiple paralogs and conserved interaction surfaces. In this case, direct generation of selective and competitive inhibitors is hindered by high similarity within the evolutionary...

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Detalles Bibliográficos
Autores principales: Rimbault, Charlotte, Maruthi, Kashyap, Breillat, Christelle, Genuer, Camille, Crespillo, Sara, Puente-Muñoz, Virginia, Chamma, Ingrid, Gauthereau, Isabel, Antoine, Ségolène, Thibaut, Coraline, Tai, Fabienne Wong Jun, Dartigues, Benjamin, Grillo-Bosch, Dolors, Claverol, Stéphane, Poujol, Christel, Choquet, Daniel, Mackereth, Cameron D., Sainlos, Matthieu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6778148/
https://www.ncbi.nlm.nih.gov/pubmed/31586061
http://dx.doi.org/10.1038/s41467-019-12528-4
Descripción
Sumario:Designing highly specific modulators of protein-protein interactions (PPIs) is especially challenging in the context of multiple paralogs and conserved interaction surfaces. In this case, direct generation of selective and competitive inhibitors is hindered by high similarity within the evolutionary-related protein interfaces. We report here a strategy that uses a semi-rational approach to separate the modulator design into two functional parts. We first achieve specificity toward a region outside of the interface by using phage display selection coupled with molecular and cellular validation. Highly selective competition is then generated by appending the more degenerate interaction peptide to contact the target interface. We apply this approach to specifically bind a single PDZ domain within the postsynaptic protein PSD-95 over highly similar PDZ domains in PSD-93, SAP-97 and SAP-102. Our work provides a paralog-selective and domain specific inhibitor of PSD-95, and describes a method to efficiently target other conserved PPI modules.