title: De novo design of peptides targeted to the EF hands of calmodulin.
abstract: This report describes the use of the concept of inversion of hydropathy patterns to the de novo design of peptides targeted to a predetermined site on a protein. Eight- and 12-residue peptides were constructed with the EF hands or Ca(2+)-coordinating sites of calmodulin as their anticipated points of interaction. These peptides, but not unrelated peptides nor those with the same amino acid composition but a scrambled sequence, interacted with the two carboxyl-terminal Ca(2+)-binding sites of calmodulin as well as the EF hands of troponin C. The interactions resulted in a conformational change whereby the 8-mer peptide-calmodulin complex could activate phosphodiesterase in the absence of Ca(2+). In contrast, the 12-mer peptide-calmodulin complex did not activate phosphodiesterase but rather inhibited activation by Ca(2+). This inhibition could be overcome by high levels of Ca(2+). Thus, it would appear that the aforementioned concept can be used to make peptide agonists and antagonists that are targeted to predetermined sites on proteins such as calmodulin.
authors.affiliation: Department of Physiology, Cancer Center, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
authors.forename: M
authors.initials: M
authors.lastname: Villain
authors.forename: P L
authors.initials: PL
authors.lastname: Jackson
authors.forename: M K
authors.initials: MK
authors.lastname: Manion
authors.forename: W J
authors.initials: WJ
authors.lastname: Dong
authors.forename: Z
authors.initials: Z
authors.lastname: Su
authors.forename: G
authors.initials: G
authors.lastname: Fassina
authors.forename: T M
authors.initials: TM
authors.lastname: Johnson
authors.forename: T T
authors.initials: TT
authors.lastname: Sakai
authors.forename: N R
authors.initials: NR
authors.lastname: Krishna
authors.forename: J E
authors.initials: JE
authors.lastname: Blalock
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002147:Calmodulin / Q000737:chemistry / Q000378:metabolism*; D002417:Cattle; D004330:Drosophila; D004789:Enzyme Activation; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D010455:Peptides / Q000138:chemical synthesis* / Q000378:metabolism; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D013050:Spectrometry, Fluorescence; D020349:Surface Plasmon Resonance; D019209:Troponin C / Q000378:metabolism
chemical_list: D002147:Calmodulin; D010455:Peptides; D019209:Troponin C; D010727:Phosphoric Diester Hydrolases