title: The key position: influence of staple location on constrained peptide conformation and binding.
abstract: Constrained α-helical peptides are showing potential as biological probes and therapeutic agents that target protein-protein interactions. However, the factors that determine the optimal constraint locations are still largely unknown. Using the β-integrin/talin protein interaction as a model system, we examine the effect of constraint location on helical conformation, as well as binding affinity, using circular dichroism and NMR spectroscopy. Stapling increased the overall helical content of each integrin-based peptide tested. However, NMR analysis revealed that different regions within the peptide are stabilised, depending on constraint location, and that these differences correlate with the changes observed in talin binding mode and affinity. In addition, we show that examination of the atomic structure of the parent peptide provides insight into the appropriate placement of helical constraints.
authors.affiliation: Department of Chemistry, School of Physical Sciences, The University of Adelaide, Adelaide, South Australia 5005, Australia.
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Keeling
authors.affiliation: Department of Molecular and Cellular Biology, School of Biological Sciences, The University of Adelaide, Adelaide, South Australia 5005, Australia. kate.wegener@adelaide.edu.au.
authors.forename: Okki
authors.initials: O
authors.lastname: Cho
authors.affiliation: Department of Chemistry, School of Physical Sciences, The University of Adelaide, Adelaide, South Australia 5005, Australia.
authors.forename: Denis B
authors.initials: DB
authors.lastname: Scanlon
authors.affiliation: Department of Molecular and Cellular Biology, School of Biological Sciences, The University of Adelaide, Adelaide, South Australia 5005, Australia. kate.wegener@adelaide.edu.au.
authors.forename: Grant W
authors.initials: GW
authors.lastname: Booker
authors.affiliation: Department of Chemistry and Centre for Nanoscale BioPhotonics, The University of Adelaide, Adelaide, South Australia 5005, Australia.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Abell
authors.affiliation: Department of Molecular and Cellular Biology, School of Biological Sciences, The University of Adelaide, Adelaide, South Australia 5005, Australia. kate.wegener@adelaide.edu.au.
authors.forename: Kate L
authors.identifier: http://orcid.org/0000-0002-1562-6060
authors.initials: KL
authors.lastname: Wegener
mesh_terms: D000595:Amino Acid Sequence; D039661:Integrin beta3 / Q000737:chemistry* / Q000378:metabolism; D007769:Lactams / Q000737:chemistry; D008958:Models, Molecular; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D017433:Protein Structure, Secondary; D059748:Proteolysis; D016608:Talin / Q000737:chemistry* / Q000378:metabolism
chemical_list: D039661:Integrin beta3; D007769:Lactams; D010446:Peptide Fragments; D016608:Talin