Structural mechanisms of QacR induction and multidrug recognition

Area of Science:

• Microbiology
• Structural Biology
• Biochemistry

Background:

• Staphylococcus aureus possesses a multidrug binding protein, QacR, which regulates the qacA multidrug transporter gene.
• QacR's transcriptional repression is induced by various cationic lipophilic drugs, suggesting a complex regulatory mechanism.

Purpose of the Study:

• To elucidate the structural basis of QacR's drug-binding and transcriptional regulation.
• To understand how QacR interacts with a diverse range of drugs.

Main Methods:

• X-ray crystallography was employed to determine the structures of six QacR-drug complexes.
• Comparison of drug-bound structures with the previously determined DNA-bound structure.

Main Results:

• Drug binding induces a significant coil-to-helix structural transition in QacR.
• This transition creates a large multidrug-binding pocket with specific amino acid residues (glutamates, aromatics, polar residues).
• The binding pocket appears to contain multiple, interconnected drug-binding sites within the QacR protein.

Conclusions:

• The crystal structures reveal a novel multisite drug-binding mechanism in QacR.
• This mechanism explains how QacR can bind diverse drugs and regulate the qacA gene.
• The findings provide insights into multidrug resistance transporter mechanisms.