Structural analysis of the sensor domain of the β-lactam antibiotic receptor VbrK from Vibrio parahaemolyticus.

Bacteria express β-lactamase to counteract the bactericidal effects of β-lactam antibiotics, which are the most widely employed antibacterial drugs. In gram-negative bacteria, the expression of β-lactamase is generally regulated in response to the muropeptide that is generated from the peptidoglycan of the cell wall during β-lactam antibiotic challenge. The direct regulation of β-lactamase expression by β-lactams was recently reported in Vibrio parahaemolyticus, and this regulation is mediated by a two-component regulatory system that consists of the histidine kinase VbrK and the response regulator VbrR. VbrK directly recognizes β-lactam antibiotics using the periplasmic sensor domain (VbrKSD), a PF11884 Pfam family member, and it delivers the β-lactam signal to VbrR to induce the transcription of the β-lactamase gene. To determine the structural features of VbrKSD as the prototype of the PF11884 family and provide insights into the β-lactam antibiotic-binding mode of VbrKSD, we determined the crystal structure of VbrKSD at 1.65 Å resolution. VbrKSD folds into a unique curved rod-like structure that has not been previously reported in other families. VbrKSD consists of two domains (D1 and D2). The D1 domain contains two helix-decorated β-sheets, and the D2 domain adopts a helix-rich structure. VbrKSD features two terminal disulfide bonds, which would be the canonical property of the PF11884 family. In the VbrKSD structure, the L82 residue, which was previously shown to play a key role in β-lactam antibiotic recognition, forms a pocket along with its neighboring hydrophobic or positively charged residues.