X-ray crystal structure of the acylated β-lactam sensor domain of BlaR1 from Staphylococcus aureus and the mechanism of receptor activation for signal transduction

Catherine Birck, Young Cha Joo, Jason Cross, Clemens Schulze-Briese, Samy O. Meroueh, H. Bernhard Schlegel, Shahriar Mobashery, Jean Pierre Samama

Research output: Contribution to journalArticle

46 Scopus citations

Abstract

Methicillin-resistant strains of Staphylococcus aureus (MRSA) are the major cause of infections worldwide. Transcription of the β-lactamase and PBP2a resistance genes is mediated by two closely related signal-transducing integral membrane proteins, BlaR1 and MecR1, upon binding of the β-lactam inducer to the sensor domain. Herein we report the crystal structure at 1.75 Å resolution of the sensor domain of BlaR1 in complex with a cephalosporin antibiotic. Activation of the signal transducer involves acylation of serine 389 by the β-lactam antibiotic, a process promoted by the N-carboxylated side chain of Lys392. We present evidence that, on acylation, the lysine side chain experiences a spontaneous decarboxylation that entraps the sensor in its activated state. Kinetic determinations and quantum mechanical/molecular mechanical calculations and the interaction networks in the crystal structure shed light on how this unprecedented process for activation of a receptor may be achieved and provide insights into the mechanistic features that differentiate the signal-transducing receptor from the structurally related class D β-lactamases, enzymes of antibiotic resistance.

Original languageEnglish (US)
Pages (from-to)13945-13947
Number of pages3
JournalJournal of the American Chemical Society
Volume126
Issue number43
DOIs
StatePublished - Nov 3 2004
Externally publishedYes

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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