Structural mechanism of the simultaneous binding of two drugs to a multidrug-binding protein.

Journal Article (Journal Article)

The structural basis of simultaneous binding of two or more different drugs by any multidrug-binding protein is unknown and also how this can lead to a noncompetitive, uncompetitive or cooperative binding mechanism. Here, we describe the crystal structure of the Staphylococcus aureus multidrug-binding transcription repressor, QacR, bound simultaneously to ethidium (Et) and proflavin (Pf). The structure underscores the plasticity of the multidrug-binding pocket and reveals an alternative, Pf-induced binding mode for Et. To monitor the simultaneous binding of Pf and Et to QacR, as well as to determine the effects on the binding affinity of one drug when the other drug is prebound, a novel application of near-ultraviolet circular dichroism (UVCD) was developed. The UVCD equilibrium-binding studies revealed identical affinities of Pf for QacR in the presence or absence of Et, but significantly diminished affinity of Et for QacR when Pf is prebound, findings that are readily explicable by their structures. The principles for simultaneous binding of two different drugs discerned here are likely employed by the multidrug efflux transporters.

Full Text

Duke Authors

Cited Authors

  • Schumacher, MA; Miller, MC; Brennan, RG

Published Date

  • August 4, 2004

Published In

Volume / Issue

  • 23 / 15

Start / End Page

  • 2923 - 2930

PubMed ID

  • 15257299

Pubmed Central ID

  • PMC514915

International Standard Serial Number (ISSN)

  • 0261-4189

Digital Object Identifier (DOI)

  • 10.1038/sj.emboj.7600288


  • eng

Conference Location

  • England