5hl9

Publication Abstract from PubMed

In Escherichia coli, the peptidoglycan cell wall is synthesized by bifunctional penicillin-binding proteins such as PBP1b that have both transpeptidase and transglycosylase activities. The PBP1b transpeptidase domain is a major target of beta-lactams and therefore it is important to attain a detailed understanding of its inhibition. The peptidoglycan glycosyltransferase domain of PBP1b is also considered an excellent antibiotic target, yet is not exploited by any clinically approved antibacterials. Herein, we adapt a pyrophosphate sensor assay to monitor PBP1b catalyzed glycosyltransfer and present an improved crystallographic model for inhibition of the PBP1b glycosyltransferase domain by the potent substrate analogue moenomycin. We elucidate the structure of a previously disordered region in the glycosyltransferase active site and discuss its implications with regards to peptidoglycan polymerization. Furthermore, we solve the crystal structures of E. coli PBP1b bound to multiple different beta-lactams in the transpeptidase active site, and complement this data with gel based competition assays to provide a detailed structural understanding of its inhibition. Taken together, this biochemical and structural data allows us to propose new insights into inhibition of both enzymatic domains in PBP1b.

Escherichia coli Penicillin-Binding Protein 1B: Structural Insights into Inhibition.,King DT, Wasney GA, Nosella M, Fong A, Strynadka NC J Biol Chem. 2016 Nov 29. pii: jbc.M116.718403. PMID:27899450^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.