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.
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.
Birck
Catherine
C
Département de Génomique et Biologie Structurales, IGBMC CNRS/INSERM/ULP, 1 rue Laurent Fries, BP 10142, 67404 - Illkirch CU Strasbourg, France.
Cha
Joo Young
JY
Cross
Jason
J
Schulze-Briese
Clemens
C
Meroueh
Samy O
SO
Schlegel
H Bernhard
HB
Mobashery
Shahriar
S
Samama
Jean-Pierre
JP
D000215:Acylation; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001426:Bacterial Proteins / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology*; D001665:Binding Sites; D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology*; D002442:Ceftazidime / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D018360:Crystallography, X-Ray; D016106:Methicillin Resistance; D046915:Penicillin-Binding Proteins / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology*; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000502:physiology; D013211:Staphylococcus aureus / Q000187:drug effects / Q000378:metabolism*; D013816:Thermodynamics; D047090:beta-Lactams / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D002352:Carrier Proteins; D046915:Penicillin-Binding Proteins; D047090:beta-Lactams; D002442:Ceftazidime