Structural mechanisms of QacR induction and multidrug recognition.
The Staphylococcus aureus multidrug binding protein QacR represses transcription of the qacA multidrug transporter gene and is induced by structurally diverse cationic lipophilic drugs. Here, we report the crystal structures of six QacR-drug complexes. Compared to the DNA bound structure, drug binding elicits a coil-to-helix transition that causes induction and creates an expansive multidrug-binding pocket, containing four glutamates and multiple aromatic and polar residues. These structures indicate the presence of separate but linked drug-binding sites within a single protein. This multisite drug-binding mechanism is consonant with studies on multidrug resistance transporters.
Schumacher
M A
MA
Department of Biochemistry and Molecular Biology, Oregon Health & Science University, Portland, OR 97201, USA.
Miller
M C
MC
Grkovic
S
S
Brown
M H
MH
Skurray
R A
RA
Brennan
R G
RG
D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism; D001599:Berberine / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D003460:Crystallization; D018360:Crystallography, X-Ray; D004247:DNA / Q000378:metabolism; D003868:Dequalinium / Q000737:chemistry / Q000378:metabolism; D019281:Dimerization; D024901:Drug Resistance, Multiple, Bacterial; D004996:Ethidium / Q000737:chemistry / Q000378:metabolism; D005840:Gentian Violet / Q000737:chemistry / Q000378:metabolism*; D005971:Glutamates / Q000737:chemistry; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000378:metabolism*; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D015394:Molecular Structure; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000737:chemistry* / Q000378:metabolism; D012235:Rhodamines / Q000737:chemistry / Q000378:metabolism; D012394:Rosaniline Dyes / Q000737:chemistry / Q000378:metabolism*; D013211:Staphylococcus aureus
D001426:Bacterial Proteins; D005971:Glutamates; D006571:Heterocyclic Compounds; C442128:QacR protein, Staphylococcus aureus; D012097:Repressor Proteins; D012235:Rhodamines; D012394:Rosaniline Dyes; D001599:Berberine; C005095:malachite green; D004247:DNA; D003868:Dequalinium; D004996:Ethidium; D005840:Gentian Violet