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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

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

Published Date

  • August 5, 2008

Published In

Volume / Issue

  • 47 / 31

Start / End Page

  • 8122 - 8129

PubMed ID

  • 18616285

Pubmed Central ID

  • PMC2646753

Electronic International Standard Serial Number (EISSN)

  • 1520-4995

Digital Object Identifier (DOI)

  • 10.1021/bi8008246


  • eng

Conference Location

  • United States