Many if not all events in biology demand highly specific interactions between macromolecular partners. Each of these events could, in theory, be targeted as part of a novel therapeutic strategy. Yet our understanding of the rules that govern interactions between macro-molecules has not advanced to the point where scientists can design molecules that predictably, potently, and selectively inhibit macromolecular complexation. In this application we build on the success of a general strategy for the design of folded, miniature proteins that bind receptors for alpha helices. This strategy, which we call protein grafting, has generated two miniature proteins based on avian pancreatic polypeptide (aPP, 36 residues) that bind DNA with exceptional affinity and specificity and one other that binds a protein with comparable properties. In this application, we explore the generality of protein recognition, by asking (Aim 1) whether miniature proteins can bind other proteins (such as Bcl-2 and Bcl-XL), even one that does not possess an identifiable """"""""deep cleft"""""""" (such as CBP).
In Aim 2 we approach the daunting problem of selective kinase inhibition, by asking whether a miniature protein can render selective an otherwise non-selective kinase inhibitor, or distinguish PKC sub-types, by recognizing the surface outside the ATP or phorbol binding pocket. Finally, we ask whether the type II polyproline (PPII) helix in aPP-based miniature proteins can be replaced functionally with a 'foldamer' to explore the virtually unexplored area of foldamer-alpha helix interactions (Aim 3) and whether miniature proteins can be assembled in an intermolecular reaction of two separate pieces (Aim 4). Construction of minimized proteins that possess appreciable biological function is an important step to-wards structure-based design of small molecules that inhibit or activate the functions regulated by protein-macromolecule complexes. The combined features of high affinity, high specificity and a compact fold implies that miniature proteins could be used to dissect, modulate, or analyze a single protein function, irrespective of the other functions the protein may regulate within the proteome.
| Hobert, Elissa M; Schepartz, Alanna (2012) Rewiring kinase specificity with a synthetic adaptor protein. J Am Chem Soc 134:3976-8 |
| Goodman, Jessica L; Molski, Matthew A; Qiu, Jade et al. (2008) Tetrameric beta(3)-peptide bundles. Chembiochem 9:1576-8 |
| Smith, Betsy A; Daniels, Douglas S; Coplin, Abigail E et al. (2008) Minimally cationic cell-permeable miniature proteins via alpha-helical arginine display. J Am Chem Soc 130:2948-9 |
| Goodman, Jessica L; Petersson, E James; Daniels, Douglas S et al. (2007) Biophysical and structural characterization of a robust octameric beta-peptide bundle. J Am Chem Soc 129:14746-51 |
| Holtzman, Jennifer H; Woronowicz, Kamil; Golemi-Kotra, Dasantila et al. (2007) Miniature protein ligands for EVH1 domains: interplay between affinity, specificity, and cell motility. Biochemistry 46:13541-53 |
| Daniels, Douglas S; Schepartz, Alanna (2007) Intrinsically cell-permeable miniature proteins based on a minimal cationic PPII motif. J Am Chem Soc 129:14578-9 |
| Hodges, Abby M; Schepartz, Alanna (2007) Engineering a monomeric miniature protein. J Am Chem Soc 129:11024-5 |
| Kritzer, Joshua A; Zutshi, Reena; Cheah, Mingtatt et al. (2006) Miniature protein inhibitors of the p53-hDM2 interaction. Chembiochem 7:29-31 |
| Guarracino, Danielle A; Chiang, Hyojin R; Banks, Tereece N et al. (2006) Relationship between salt-bridge identity and 14-helix stability of beta3-peptides in aqueous buffer. Org Lett 8:807-10 |
| Qiu, Jade X; Petersson, E James; Matthews, Erin E et al. (2006) Toward beta-amino acid proteins: a cooperatively folded beta-peptide quaternary structure. J Am Chem Soc 128:11338-9 |
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