High-resolution crystal structure reveals molecular details of target recognition by bacitracin.
Bacitracin is a metalloantibiotic agent that is widely used as a medicine and feed additive. It interferes with bacterial cell-wall biosynthesis by binding undecaprenyl-pyrophosphate, a lipid carrier that serves as a critical intermediate in cell wall production. Despite bacitracin's broad use, the molecular details of its target recognition have not been elucidated. Here we report a crystal structure for the ternary complex of bacitracin A, zinc, and a geranyl-pyrophosphate ligand at a resolution of 1.1 Å. The antibiotic forms a compact structure that completely envelopes the ligand's pyrophosphate group, together with flanking zinc and sodium ions. The complex adopts a highly amphipathic conformation that offers clues to antibiotic function in the context of bacterial membranes. Bacitracin's efficient sequestration of its target represents a previously unseen mode for the recognition of lipid pyrophosphates, and suggests new directions for the design of next-generation antimicrobial agents.
Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102, USA.
Nicoleta J
NJ
Economou
Simon
S
Cocklin
Patrick J
PJ
Loll
D000595:Amino Acid Sequence; D001414:Bacitracin / Q000737:chemistry / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011106:Polyisoprenyl Phosphates / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D020349:Surface Plasmon Resonance
D011106:Polyisoprenyl Phosphates; D001414:Bacitracin; C088139:undecaprenyl pyrophosphate; C026461:bacitracin A
X-ray crystallography; antibiotic resistance; molecular recognition