CRYSTAL STRUCTURE OF BIFUNCTIONAL TRANSGLYCOSYLASE PBP1B FROM E. COLI AND INHIBITORS THEREOF

摘要

Crystal structure at 2.16 Å resolution of full-length Escherichia coli penicillin-binding protein 1b (PBP1b) in complex with its inhibitor moenomycin, is provided. 3D structures of amino acid residues involved in moenomycin binding and transglycosylation activity are identified. Binding sites for peptidoglycan synthesis inhibitors comprising amino acid residues from transglycosylase (TG), UvrB domain 2 homolog (UB2H) and transmembrane (TM) domains of PBP1b are identified at atomic level resolution. Rational drug design, based on the atomic coordinates, are disclosed. Methods for screening for antibiotics using anisotropic binding and transglycosylase inhibitor assays and novel antibiotics based on the screening assays are provided.

主权项

1. A method for identifying a transglycosylase (peptidoglycan glycosyltransferase) inhibitor compound, the method comprising the steps of:
a) employing a three-dimensional structure of E. coli Penicillin binding protein 1b (PBP1b) as defined by atomic coordinates according to FIGS. 8-1 through 8-82, to design or select said potential inhibitor such that said potential inhibitor is capable of binding to at least one amino acid located in an active site of PBP1b transglycosylase; b) determining an ability of the potential inhibitor to bind PBP1b; and c) determining a PBP1b transglycosylase inhibitory activity of the potential inhibitor.