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 Meroueh, H. Bernhard Schlegel, Shahriar Mobashery, Jean Pierre Samama

Research output: Contribution to journalArticle

45 Citations (Scopus)

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

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Lactams
Signal transduction
Acylation
Antibiotics
4 alpha-glucanotransferase
Staphylococcus aureus
Signal Transduction
Crystal structure
Chemical activation
X-Rays
X rays
Decarboxylation
Sensors
Cephalosporins
Methicillin-Resistant Staphylococcus aureus
Microbial Drug Resistance
Transducers
Serine
Anti-Bacterial Agents
Lysine

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

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

In: Journal of the American Chemical Society, Vol. 126, No. 43, 03.11.2004, p. 13945-13947.

Research output: Contribution to journalArticle

Birck, Catherine ; Joo, Young Cha ; Cross, Jason ; Schulze-Briese, Clemens ; Meroueh, Samy ; Schlegel, H. Bernhard ; Mobashery, Shahriar ; Samama, Jean Pierre. / 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. In: Journal of the American Chemical Society. 2004 ; Vol. 126, No. 43. pp. 13945-13947.
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