X-ray crystal structure of the acylated beta-lactam sensor domain of BlaR1 from Staphylococcus aureus and the mechanism of receptor activation for signal transduction.
J Am Chem Soc
; 126(43): 13945-7, 2004 Nov 03.
Article
de En
| MEDLINE
| ID: mdl-15506754
ABSTRACT
Methicillin-resistant strains of Staphylococcus aureus (MRSA) are the major cause of infections worldwide. Transcription of the beta-lactamase and PBP2a resistance genes is mediated by two closely related signal-transducing integral membrane proteins, BlaR1 and MecR1, upon binding of the beta-lactam inducer to the sensor domain. Herein we report the crystal structure at 1.75 A 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 beta-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 beta-lactamases, enzymes of antibiotic resistance.
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Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Staphylococcus aureus
/
Protéines bactériennes
/
Protéines de transport
/
Bêta-Lactames
/
Protéines de liaison aux pénicillines
Langue:
En
Journal:
J Am Chem Soc
Année:
2004
Type de document:
Article
Pays d'affiliation:
France