title: Absence of a stable secondary structure is not a limitation for photoswitchable inhibitors of β-arrestin/β-Adaptin 2 protein-protein interaction.
abstract: Many protein-protein interactions (PPIs) are mediated by short, often helical, linear peptides. Molecules mimicking these peptides have been used to inhibit their PPIs. Recently, photoswitchable peptides with little secondary structure have been developed as modulators of clathrin-mediated endocytosis. Here we perform a systematic analysis of a series of azobenzene-crosslinked peptides based on a β-arrestin P-long 20-mer peptide (BAP-long) sequence to assess the relevance of secondary structure in their interaction with β-adaptin 2 and to identify the design requirements for photoswitchable inhibitors of PPI (PIPPIs). We observe that flexible structures show a greater inhibitory capacity and enhanced photoswitching ability and that the absence of helical structures in free inhibitor peptide is not a limitation for PIPPI candidates. Therefore, our PIPPIs expand the field of potential inhibitors of PPIs to the wide group of flexible peptides, and we argue against using a stable secondary structure as a sole criterion when designing PIPPI candidates.
authors.affiliation: Institute for Bioengineering of Catalonia (IBEC), Barcelona 08028, Spain.
authors.forename: Andrés
authors.initials: A
authors.lastname: Martín-Quirós
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), Barcelona 08028, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Nevola
authors.affiliation: Institute for Bioengineering of Catalonia (IBEC), Barcelona 08028, Spain; Network Biomedical Research Center on Bioengineering, Biomaterials, and Nanomedicine (CIBER-BBN), Madrid 28029, Spain.
authors.forename: Kay
authors.initials: K
authors.lastname: Eckelt
authors.affiliation: Institute for Theoretical and Computational Chemistry (IQTCUB), Barcelona 08028, Spain; Department of Physical Chemistry, University of Barcelona (UB), Barcelona 08028, Spain.
authors.forename: Sergio
authors.initials: S
authors.lastname: Madurga
authors.affiliation: Institute for Bioengineering of Catalonia (IBEC), Barcelona 08028, Spain; Network Biomedical Research Center on Bioengineering, Biomaterials, and Nanomedicine (CIBER-BBN), Madrid 28029, Spain; Catalan Institution for Research and Advanced Studies (ICREA), Barcelona 08010, Spain. Electronic address: pau@icrea.cat.
authors.forename: Pau
authors.initials: P
authors.lastname: Gorostiza
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), Barcelona 08028, Spain; Department of Organic Chemistry, University of Barcelona (UB), Barcelona 080280, Spain. Electronic address: ernest.giralt@irbbarcelona.org.
authors.forename: Ernest
authors.initials: E
authors.lastname: Giralt
mesh_terms: D033966:Adaptor Protein Complex beta Subunits / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000595:Amino Acid Sequence; D019390:Arrestins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001391:Azo Compounds / Q000737:chemistry; D002942:Circular Dichroism; D015195:Drug Design; D007536:Isomerism; D007700:Kinetics; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D054730:Protein Interaction Domains and Motifs / Q000187:drug effects; D017433:Protein Structure, Secondary; D014466:Ultraviolet Rays; D000071557:beta-Arrestins
chemical_list: D033966:Adaptor Protein Complex beta Subunits; D019390:Arrestins; D001391:Azo Compounds; D010455:Peptides; D000071557:beta-Arrestins; C009850:azobenzene