Determining the structure and mechanism of the human multidrug resistance P-glycoprotein using cysteine-scanning mutagenesis and thiol-modification techniques

Biochim Biophys Acta. 1999 Dec 6;1461(2):315-25. doi: 10.1016/s0005-2736(99)00165-0.

Abstract

The multidrug resistance P-glycoprotein is an ATP-dependent drug pump that extrudes a broad range of hydrophobic compounds out of cells. Its physiological role is likely to protect us from exogenous and endogenous toxins. The protein is important because it contributes to the phenomenon of multidrug resistance during AIDS and cancer chemotherapy. We have used cysteine-scanning mutagenesis and thiol-modification techniques to map the topology of the protein, show that both nucleotide-binding domains are essential for activity, examine packing of the transmembrane segments, map the drug-binding site, and show that there is cross-talk between the ATP-binding sites and the transmembrane segments.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / chemistry
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • ATP-Binding Cassette Transporters / chemistry
  • ATP-Binding Cassette Transporters / metabolism*
  • Binding Sites
  • Carrier Proteins / metabolism
  • Cell Membrane / chemistry
  • Cysteine / chemistry
  • Disulfides / chemistry
  • Drug Resistance, Multiple
  • Humans
  • Mutagenesis, Site-Directed
  • Protein Conformation
  • Protein Folding

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • ATP-Binding Cassette Transporters
  • Carrier Proteins
  • Disulfides
  • NUBP1 protein, human
  • Cysteine