title: Serendipitous discovery of novel bacterial methionine aminopeptidase inhibitors.
abstract: In this article we describe the application of structural biology methods to the discovery of novel potent inhibitors of methionine aminopeptidases. These enzymes are employed by the cells to cleave the N-terminal methionine from nascent peptides and proteins. As this is one of the critical steps in protein maturation, it is very likely that inhibitors of these enzymes may prove useful as novel antibacterial agents. Involvement of crystallography at the very early stages of the inhibitor design process resulted in serendipitous discovery of a new inhibitor class, the pyrazole-diamines. Atomic-resolution structures of several inhibitors bound to the enzyme illuminate a new mode of inhibitor binding.
authors.affiliation: Structural Biology Core Facility, The Procter & Gamble Pharmaceuticals, Mason, Ohio 45040, USA. artem@xtals.org
authors.forename: Artem G
authors.initials: AG
authors.lastname: Evdokimov
authors.forename: Matthew
authors.initials: M
authors.lastname: Pokross
authors.forename: Richard L
authors.initials: RL
authors.lastname: Walter
authors.forename: Marlene
authors.initials: M
authors.lastname: Mekel
authors.forename: Bobby L
authors.initials: BL
authors.lastname: Barnett
authors.forename: Jack
authors.initials: J
authors.lastname: Amburgey
authors.forename: William L
authors.initials: WL
authors.lastname: Seibel
authors.forename: Shari J
authors.initials: SJ
authors.lastname: Soper
authors.forename: Jane F
authors.initials: JF
authors.lastname: Djung
authors.forename: Neil
authors.initials: N
authors.lastname: Fairweather
authors.forename: Conrad
authors.initials: C
authors.lastname: Diven
authors.forename: Vinit
authors.initials: V
authors.lastname: Rastogi
authors.forename: Leo
authors.initials: L
authors.lastname: Grinius
authors.forename: Charles
authors.initials: C
authors.lastname: Klanke
authors.forename: Richard
authors.initials: R
authors.lastname: Siehnel
authors.forename: Tracy
authors.initials: T
authors.lastname: Twinem
authors.forename: Ryan
authors.initials: R
authors.lastname: Andrews
authors.forename: Alan
authors.initials: A
authors.lastname: Curnow
mesh_terms: D000626:Aminopeptidases / Q000737:chemistry / Q000302:isolation & purification; D001419:Bacteria / Q000187:drug effects / Q000201:enzymology*; D001426:Bacterial Proteins / Q000494:pharmacology; D003460:Crystallization; D018360:Crystallography, X-Ray; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D063208:Methionyl Aminopeptidases; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011487:Protein Conformation; D011789:Quantum Theory
chemical_list: D001426:Bacterial Proteins; D011480:Protease Inhibitors; D000626:Aminopeptidases; D063208:Methionyl Aminopeptidases