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These bifunctional enzymes add new material to the pre-existing PG in two coordinated, yet successive steps. The final enzymatic steps in PG synthesis are carried out by polysaccharide polymerases called class A penicillin-binding proteins (PBPs). Because of its essential role, accessible periplasmic location, and lack of human orthologs, the PG biosynthetic pathway is targeted by the majority of human antibacterials in clinical use. In Gram-negative bacteria such as Escherichia coli, the thin PG layer is sandwiched between the inner and outer membranes and is an essential feature that is inexorably linked to both cell growth and morphogenesis ( 1). Most bacteria are encased in a peptide cross-linked glycan net known as the peptidoglycan (PG) 2 sacculus. Taken together, these biochemical and structural data allow us to propose new insights into inhibition of both enzymatic domains in PBP1b. coli PBP1b bound to multiple different β-lactams in the transpeptidase active site and complement these data with gel-based competition assays to provide a detailed structural understanding of its inhibition. Furthermore, we solve the crystal structures of E. We elucidate the structure of a previously disordered region in the glycosyltransferase active site and discuss its implications with regards to peptidoglycan polymerization. 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 analog moenomycin. The peptidoglycan glycosyltransferase domain of PBP1b is also considered an excellent antibiotic target yet is not exploited by any clinically approved antibacterials. The PBP1b transpeptidase domain is a major target of β-lactams, and therefore it is important to attain a detailed understanding of its inhibition. In Escherichia coli, the peptidoglycan cell wall is synthesized by bifunctional penicillin-binding proteins such as PBP1b that have both transpeptidase and transglycosylase activities.