title: Minimum requirements for inhibition of smooth-muscle myosin light-chain kinase by synthetic peptides.
abstract: Although the amino acid residues that are important for peptide substrates of myosin light-chain kinase have been reported, those that are important for peptide inhibitors of this enzyme have not previously been investigated. Synthetic peptides based on the sequence Lys11-Lys12-Arg13-Ala-Ala-Arg16-Ala-Thr-Ser19 -Asn-Val21-Phe22-Ala of the chicken gizzard myosin light chain were tested as inhibitors of pig carotid-artery myosin light-chain kinase. The basic amino acid residues of the known myosin light-chain kinase inhibitor Lys-Lys-Arg-Ala-Ala-Arg-Ala-Thr-Ser-NH2 (IC50 = 14 microM) [Pearson, Misconi & Kemp (1986) J. Biol. Chem. 261, 25-27] were shown to be the important residues that contribute to inhibitor potency, as evidence by the finding that the hexapeptide Lys-Lys-Arg-Ala-Ala-Arg-NH2 had an IC50 value of 22 microM. This indicates that binding of the phosphorylatable serine residue to myosin light-chain kinase, which is of obvious importance for a substrate, does not enhance the potency of an inhibitor. With the aim of preparing more potent inhibitors, peptides Lys-Lys-Arg-Ala-Ala-Arg-Ala-Ala-Xaa-NH2 were prepared with a variety of amino acids substituted for the phosphorylatable serine residue. None of these peptides was a more potent inhibitor than the serine peptide.
authors.affiliation: Squibb Institute for Medical Research, Department of Chemistry, Princeton, NJ 08543-4000.
authors.forename: J T
authors.initials: JT
authors.lastname: Hunt
authors.forename: D M
authors.initials: DM
authors.lastname: Floyd
authors.forename: V G
authors.initials: VG
authors.lastname: Lee
authors.forename: D K
authors.initials: DK
authors.lastname: Little
authors.forename: S
authors.initials: S
authors.lastname: Moreland
mesh_terms: D000107:Acetylation; D000595:Amino Acid Sequence; D000818:Animals; D008969:Molecular Sequence Data; D009130:Muscle, Smooth / Q000201:enzymology*; D009219:Myosin-Light-Chain Kinase / Q000037:antagonists & inhibitors*; D010455:Peptides / Q000494:pharmacology*; D010766:Phosphorylation
chemical_list: D010455:Peptides; D009219:Myosin-Light-Chain Kinase