P-glycoprotein function involves conformational transitions detectable by differential immunoreactivity

Eugene B. Mechetner, Brigitte Schott, Brian S. Morse, Wilfred D. Stein, Todd Druley, Kenneth A. Davis, Takashi Tsuruo, Igor B. Roninson

Research output: Contribution to journalArticlepeer-review

161 Scopus citations

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.

Original languageEnglish
Pages (from-to)12908-12913
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume94
Issue number24
DOIs
StatePublished - Nov 25 1997
Externally publishedYes

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