title: Structural basis of the intrasteric regulation of myosin light chain kinases.
abstract: The smooth muscle myosin light chain kinase (smMLCK) catalytic core was modeled by using the crystallographic coordinates of the cyclic AMP-dependent protein kinase catalytic subunit (cAPK) and a bound pseudosubstrate inhibitor peptide, PKI(5-24). Despite only 30% identity in amino acid sequence, the MLCK sequence can be readily accommodated in this structure. With the exception of the short B-helix, all major elements of secondary structure in the core are very likely conserved. The active site of the modeled MLCK complements the known requirements for peptide substrate recognition. MLCK contains a pseudosubstrate sequence that overlaps the calmodulin binding domain and has been proposed to act as an intrasteric inhibitor and occupy the substrate binding site in the absence of Ca(2+)-calmodulin. The pseudosubstrate sequence can be modeled easily into the entire backbone of PKI(5-24). The results demonstrate that the intrasteric model for regulation of MLCK by intramolecular competitive inhibition is structurally plausible.
authors.affiliation: Department of Chemistry, University of California San Diego, La Jolla 92093-0654.
authors.forename: D R
authors.initials: DR
authors.lastname: Knighton
authors.forename: R B
authors.initials: RB
authors.lastname: Pearson
authors.forename: J M
authors.initials: JM
authors.lastname: Sowadski
authors.forename: A R
authors.initials: AR
authors.lastname: Means
authors.forename: L F
authors.initials: LF
authors.lastname: Ten Eyck
authors.forename: S S
authors.initials: SS
authors.lastname: Taylor
authors.forename: B E
authors.initials: BE
authors.lastname: Kemp
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D002874:Chromosome Mapping; D003461:Crystallography; D015971:Gene Expression Regulation, Enzymologic; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009219:Myosin-Light-Chain Kinase / Q000737:chemistry*; D009842:Oligopeptides / Q000235:genetics / Q000378:metabolism; D010446:Peptide Fragments; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D011494:Protein Kinases / Q000737:chemistry; D016415:Sequence Alignment; D017385:Sequence Homology
chemical_list: D009842:Oligopeptides; D010446:Peptide Fragments; D010455:Peptides; C061479:protein kinase inhibitor peptide; C037642:kemptide; D011494:Protein Kinases; D009219:Myosin-Light-Chain Kinase