QacR-cation recognition is mediated by a redundancy of residues capable of charge neutralization.

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Peters KM, Schuman JT, Skurray RA, Brown MH, Brennan RG, Schumacher MA

QacR-cation recognition is mediated by a redundancy of residues capable of charge neutralization.

Biochemistry. 2008 Aug 5;47(31):8122-9. doi: 10.1021/bi8008246. Epub 2008 Jul 11.

PubMed ID

18616285 [ View in PubMed

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Abstract

The Staphylococcus aureus multidrug binding protein QacR binds to a broad spectrum of structurally dissimilar cationic, lipophilic drugs. Our previous structural analyses suggested that five QacR glutamic acid residues are critical for charge neutralization and specification of certain drugs. For example, E57 and E58 interact with berberine and with one of the positively charged moieties of the bivalent drug dequalinium. Here we report the structural and biochemical effects of substituting E57 and E58 with alanine and glutamine. Unexpectedly, individual substitutions of these residues did not significantly affect QacR drug binding affinity. Structures of QacR(E57Q) and QacR(E58Q) bound to dequalinium indicated that E57 and E58 are redundant for charge neutralization. The most significant finding was that berberine was reoriented in the QacR multidrug binding pocket so that its positive charge was neutralized by side chain oxygen atoms and aromatic residues. Together, these data emphasize the remarkable versatility of the QacR multidrug binding pocket, illustrating that the capacity of QacR to bind myriad cationic drugs is largely governed by the presence in the pocket of a redundancy of polar, charged, and aromatic residues that are capable of electrostatic neutralization.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Dequalinium	HTH-type transcriptional regulator QacR	Protein	Staphylococcus aureus	Unknown	Regulator	Details