Active site restructuring regulates ligand recognition in class A penicillin-binding proteins.
Bacterial cell division is a complex, multimolecular process that requires biosynthesis of new peptidoglycan by penicillin-binding proteins (PBPs) during cell wall elongation and septum formation steps. Streptococcus pneumoniae has three bifunctional (class A) PBPs that catalyze both polymerization of glycan chains (glycosyltransfer) and cross-linking of pentapeptidic bridges (transpeptidation) during the peptidoglycan biosynthetic process. In addition to playing important roles in cell division, PBPs are also the targets for beta-lactam antibiotics and thus play key roles in drug-resistance mechanisms. The crystal structure of a soluble form of pneumococcal PBP1b (PBP1b*) has been solved to 1.9 A, thus providing previously undescribed structural information regarding a class A PBP from any organism. PBP1b* is a three-domain molecule harboring a short peptide from the glycosyltransferase domain bound to an interdomain linker region, the transpeptidase domain, and a C-terminal region. The structure of PBP1b* complexed with beta-lactam antibiotics reveals that ligand recognition requires a conformational modification involving conserved elements within the cleft. The open and closed structures of PBP1b* suggest how class A PBPs may become activated as novel peptidoglycan synthesis becomes necessary during the cell division process. In addition, this structure provides an initial framework for the understanding of the role of class A PBPs in the development of antibiotic resistance.
Macheboeuf
Pauline
P
Laboratoires de Cristallographie Macromoléculaire, Centre National de la Recherche Scientifique/Commissariat à l'Energie Atomique/Université Joseph Fourier, 41 Rue Jules Horowitz, 38027 Grenoble, France.
Di Guilmi
Anne Marie
AM
Job
Viviana
V
Vernet
Thierry
T
Dideberg
Otto
O
Dessen
Andréa
A
D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D008024:Ligands; D015394:Molecular Structure; D020125:Mutation, Missense; D046915:Penicillin-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000502:physiology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D013296:Streptococcus pneumoniae / Q000737:chemistry*; D018440:beta-Lactam Resistance; D047090:beta-Lactams / Q000737:chemistry
D008024:Ligands; D046915:Penicillin-Binding Proteins; D047090:beta-Lactams