P-glycoprotein function involves conformational transitions detectable by differential immunoreactivity.

E B Mechetner; B Schott; B S Morse; W D Stein; T Druley; K A Davis; T Tsuruo; I B Roninson

doi:10.1073/pnas.94.24.12908

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PubMed · 9371774

P-glycoprotein function involves conformational transitions detectable by differential immunoreactivity.

E B Mechetner·B Schott·B S Morse·W D Stein·T Druley·K A Davis·T Tsuruo·I B Roninson

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Abstract

The MDR1 P-glycoprotein (Pgp), a member of the ATP-binding cassette family of transporters, is a transmembrane ATPase efflux pump for various lipophilic compounds, including many anti-cancer drugs. mAb UIC2, reactive with the extracellular moiety of Pgp, inhibits Pgp-mediated efflux. UIC2 reactivity with Pgp was increased by the addition of several Pgp-transported compounds or ATP-depleting agents, and by mutational inactivation of both nucleotide-binding domains (NBDs) of Pgp. UIC2 binding to Pgp mutated in both NBDs was unaffected in the presence of Pgp transport substrates or in ATP-depleted cells, whereas the reactivities of the wild-type Pgp and Pgps mutated in a single NBD were increased by these treatments to the level of the double mutant. These results indicate the existence of different Pgp conformations associated with different stages of transport-associated ATP hydrolysis and suggest trapping in a transient conformation as a mechanism for antibody-mediated inhibition of Pgp.

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ATP Binding Cassette Transporter, Subfamily B, Member 1 Adenosine Triphosphate Antibodies, Monoclonal Binding Sites Biological Transport Humans Hydrolysis Protein Binding Protein Conformation Tumor Cells, Cultured Journal Article Research Support, U.S. Gov't, P.H.S.

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E B Mechetner, B Schott, B S Morse, W D Stein, T Druley, K A Davis, T Tsuruo, I B Roninson. 1997-11-25. P-glycoprotein function involves conformational transitions detectable by differential immunoreactivity.. https://doi.org/10.1073/pnas.94.24.12908

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