title: Co-crystallization of Staphylococcus aureus peptide deformylase (PDF) with potent inhibitors.
abstract: In bacteria the biosynthesis of all nascent polypeptides begins with N-formylmethionine. The post-translational removal of the N-formyl group is carried out by peptide deformylase (PDF). Processing of the N-formyl group from critical bacterial proteins is required for cell survival. This formylation/deformylation cycle is unique to eubacteria and is not utilized in eucaryotic cytosolic protein biosynthesis. Thus, inhibition of PDF would halt bacterial growth, spare host cell-function, and would be a novel mechanism for a new class of antibiotic. Diffraction-quality Se-met crystals of S. aureus PDF were prepared that belong to space group C222(1) with unit cell parameters of a = 94.1 b = 121.9 c = 47.6 A. Multiple anomalous dispersion data were collected at the Advanced Photon Source 17-ID beamline and used to solve the PDF structure to 1.9 A resolution. Crystals were also prepared with three PDF inhibitors: thiorphan, actinonin and PNU-172550. The thiorphan and actinonin co-crystals belong to space group C222(1) with similar unit-cell dimensions. Repeated attempts to generate a complex structure of PDF with PNU-172550 from the orthorhombic space group were unsuccessful. Crystallization screening identified an alternate C2 crystal form with unit-cell dimensions of a = 93.4 b = 42.5 c = 104.1 A, beta = 93 degrees.
authors.affiliation: Structural, Analytical and Medicinal Chemistry, Pharmacia Corporation, 301 Henrietta Street, Kalamazoo, MI 49007, USA. melissa.s.harris@pharmacia.com
authors.forename: Melissa S
authors.initials: MS
authors.lastname: Harris
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Bock
authors.forename: Gil
authors.initials: G
authors.lastname: Choi
authors.forename: Joyce S
authors.initials: JS
authors.lastname: Cialdella
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Curry
authors.forename: Martin R
authors.initials: MR
authors.lastname: Deibel
authors.forename: E Jon
authors.initials: EJ
authors.lastname: Jacobsen
authors.forename: Vincent P
authors.initials: VP
authors.lastname: Marshall
authors.forename: Robert W
authors.initials: RW
authors.lastname: Murray
authors.forename: Anne F
authors.initials: AF
authors.lastname: Vosters
authors.forename: Cindy L
authors.initials: CL
authors.lastname: Wolfe
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Yem
authors.forename: Eric T
authors.initials: ET
authors.lastname: Baldwin
mesh_terms: D000581:Amidohydrolases; D000626:Aminopeptidases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D003460:Crystallization; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D011487:Protein Conformation; D013211:Staphylococcus aureus / Q000201:enzymology*
chemical_list: D004791:Enzyme Inhibitors; D000626:Aminopeptidases; D000581:Amidohydrolases; C084507:peptide deformylase