Proceedings of the National Academy of Sciences · 1997 · 185 citations · 35 references
MedicineBiochemistryPharmacologyCancer PharmacologyIntracellular TransportMolecular PharmacologyAtp HydrolysisCellular Drug EffluxMembrane TransportTransport Across Biological MembranesTransport In CellsTransporter PharmacologyAdenosine Triphosphate-binding Cassette TransportersAtp-binding Cassette TransportersConformational TransitionsNucleotide Binding DomainsP-glycoprotein TransportP-glycoprotein-mediated EffluxTransport AtpasesTransporter-mediated Efflux
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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Lutz Nährlich, Jochen G. Mainz, Constantin Adams et al. · Cellular Physiology and Biochemistry · 2013 · 2.5K citations · Full text