title: Adaptation of the behaviour of an aspartic proteinase inhibitor by relocation of a lysine residue by one helical turn.
abstract: In addition to self-inhibition of aspartic proteinase zymogens by their intrinsic proparts, the activity of certain members of this enzyme family can be modulated through active-site occupation by extrinsic polypeptides such as the small IA3 protein from Saccharomyces cerevisiae. The unprecedented mechanism by which IA3 helicates to inhibit its sole target aspartic proteinase locates an i, i+4 pair of charged residues (Lys18+Asp22) on an otherwise-hydrophobic face of the amphipathic helix. The nature of these residues is not crucial for effective inhibition, but re-location of the lysine residue by one turn (+4 residues) in the helical IA3 positions its side chain in the mutant IA3-proteinase complex in an orientation essentially identical to that of the key lysine residue in zymogen proparts. The binding of the extrinsic mutant IA3 shows pH dependence reminiscent of that required for the release of intrinsic zymogen proparts so that activation can occur.
authors.affiliation: School of Biosciences, Cardiff University, Cardiff CF10 3US, Wales, UK.
authors.forename: Tim J
authors.initials: TJ
authors.lastname: Winterburn
authors.forename: David M
authors.initials: DM
authors.lastname: Wyatt
authors.forename: Lowri H
authors.initials: LH
authors.lastname: Phylip
authors.forename: Colin
authors.initials: C
authors.lastname: Berry
authors.forename: Daniel
authors.initials: D
authors.lastname: Bur
authors.forename: John
authors.initials: J
authors.lastname: Kay
mesh_terms: D000222:Adaptation, Physiological / Q000502:physiology*; D001224:Aspartic Acid / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006863:Hydrogen-Ion Concentration; D008239:Lysine / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D013329:Structure-Activity Relationship
chemical_list: D011480:Protease Inhibitors; D001224:Aspartic Acid; D016282:Aspartic Acid Endopeptidases; D008239:Lysine