title: The 1.15A crystal structure of the Staphylococcus aureus methionyl-aminopeptidase and complexes with triazole based inhibitors.
abstract: Methionyl aminopeptidases (MetAPs) represent a unique class of protease that are responsible for removing the N-terminal methionine residue from proteins and peptides. There are two major classes of MetAPs (type I and type II) described and each class can be subdivided into two subclasses. Eukaryotes contain both the type I and type II MetAPs, whereas prokaryotes possess only the type I enzyme. Due to the physiological importance of these enzymes there is considerable interest in inhibitors to be used as antiangiogenic and antimicrobial agents. Here, we describe the 1.15A crystal structure of the Staphylococcus aureus MetAP-I as an apo-enzyme and its complexes with various 1,2,4-triazole-based derivatives at high-resolution. The protein has a typical "pita-bread" fold as observed for the other MetAP structures. The inhibitors bind in the active site with the N1 and N2 atoms of the triazole moiety complexing two divalent ions. The 1,2,4-triazols represent a novel class of potent non-peptidic inhibitors for the MetAP-Is.
authors.affiliation: Morphochem AG, WRO-1055/338 Schwarzwaldallee 215, 4058 Basel, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Oefner
authors.forename: Alice
authors.initials: A
authors.lastname: Douangamath
authors.forename: Allan
authors.initials: A
authors.lastname: D'Arcy
authors.forename: Sascha
authors.initials: S
authors.lastname: Häfeli
authors.forename: Daniel
authors.initials: D
authors.lastname: Mareque
authors.forename: Aengus
authors.initials: A
authors.lastname: Mac Sweeney
authors.forename: Juan
authors.initials: J
authors.lastname: Padilla
authors.forename: Sabine
authors.initials: S
authors.lastname: Pierau
authors.forename: Henk
authors.initials: H
authors.lastname: Schulz
authors.forename: Michael
authors.initials: M
authors.lastname: Thormann
authors.forename: Sjoerd
authors.initials: S
authors.lastname: Wadman
authors.forename: Glenn E
authors.initials: GE
authors.lastname: Dale
mesh_terms: D000595:Amino Acid Sequence; D000626:Aminopeptidases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D001051:Apoenzymes; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006801:Humans; D046911:Macromolecular Substances; D063208:Methionyl Aminopeptidases; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D011487:Protein Conformation; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D013211:Staphylococcus aureus / Q000201:enzymology*; D014230:Triazoles / Q000737:chemistry*
chemical_list: D001051:Apoenzymes; D004791:Enzyme Inhibitors; D046911:Macromolecular Substances; D014230:Triazoles; D000626:Aminopeptidases; D063208:Methionyl Aminopeptidases