Penicillin binding proteins (PBPs) catalyze two reactions that are needed to form bacterial cell walls. β-Lactam antibiotics shut down one of these reactions by irreversibly acylating a serine unit in a protein’s active site. Methicillin-resistant Staphylococcus aureus, or MRSA, expresses a form of this protein, PBP2a, that is resistant to β-lactams. Shahriar Mobashery of the University of Notre Dame, Juan A. Hermoso of the Spanish National Research Council, and coworkers now report that an allosteric binding site controls access to PBP2a’s active site for both its natural substrate and β-lactam antibiotics (Proc. Natl. Acad. Sci. USA 2013, DOI: 10.1073/pnas.1300118110). When the allosteric site is occupied, the enzyme undergoes a conformational change that opens the active site 60 Å away, which is considered a long distance for a protein allosteric effect. X-ray crystallography structures reveal that muramic acid, peptidoglycan from the cell wall, and the β-lactam antibiotic ceftaroline can all serve as allosteric ligands. For example, when one ceftaroline molecule binds, it paves the way for a second molecule to inactivate the enzyme. The ability of an antibiotic to open the active site suggests a new route for structure-based drug design.