title: Structure-oriented rational design of chymotrypsin inhibitor models.
abstract: Three peptides modelling a highly potent, 35-residue chymotrypsin inhibitor (Schistocerca gregaria chymotrypsin inhibitor) were designed and synthesized by convergent peptide synthesis. For each model peptide, the inhibitory constant (Ki) on chymotrypsin and the solution structure were determined. In addition, molecular dynamics calculations were performed for all of them. Two models containing approximately half of the parent inhibitor (17 of 35 residues) were designed and subsequently found to have no substantial inhibitory activity (Ki values in the mM range). The third model composed of 24 amino acid residues proved to be an effective (Ki approximately 10(-7)) inhibitor of bovine chymotrypsin. Both the solution structure properties determined by NMR spectroscopy and the dynamic behaviour of the latter model system are comparable to the native inhibitor. In contrast, the structure and dynamics of the first two related model peptides show characteristic differences. We suggest that the conformation and flexibility of the modelled protease inhibitor are crucial for its biological efficiency. Moreover, the structural and dynamic features of the binding loop (28-33) and those of the rest of the molecule appear to be interdependent. Most importantly, these structural characteristics can be rationally modified, at least partially, by peptide design.
authors.affiliation: Department of Organic Chemistry, Hungarian Academy of Sciences, Eötvös Loránd University, Pázmány Péter sétány 1/A, H-1117 Budapest, Hungary.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Mucsi
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Gáspári
authors.forename: György
authors.initials: G
authors.lastname: Orosz
authors.forename: András
authors.initials: A
authors.lastname: Perczel
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002417:Cattle; D002918:Chymotrypsin / Q000737:chemistry*; D002942:Circular Dichroism; D019476:Insect Proteins / Q000737:chemistry* / Q000494:pharmacology; D007313:Insecta; D008956:Models, Chemical; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D010455:Peptides / Q000737:chemistry*; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D017510:Protein Folding; D013329:Structure-Activity Relationship
chemical_list: D002918:Chymotrypsin; D019476:Insect Proteins; D010455:Peptides; D011480:Protease Inhibitors; C113210:LOC126284306 protein, Schistocerca gregaria