Competitive, non-competitive and cooperative interactions between substrates of P-glycoprotein as measured by its ATPase activity.

@article{Litman1997CompetitiveNA,
  title={Competitive, non-competitive and cooperative interactions between substrates of P-glycoprotein as measured by its ATPase activity.},
  author={Thomas Litman and Thomas Zeuthen and Torben Skovsgaard and Wilfred Donald Stein},
  journal={Biochimica et biophysica acta},
  year={1997},
  volume={1361 2},
  pages={
          169-76
        }
}
Cooperativity in the inhibition of P-glycoprotein-mediated daunorubicin transport: evidence for half-of-the-sites reactivity.
TLDR
The data support the mechanistic proposal that substrate binding at one putative transport binding site precludes activity at another unequal site; many of the substrates examined exert a negative allosteric effect on the other transport site (and vice versa).
Co-operative binding sites for transported substrates in the multiple drug resistance transporter Mdr1.
  • E. Buxbaum
  • Biology, Chemistry
    European journal of biochemistry
  • 1999
TLDR
The results indicate the existence of multiple binding sites (at least four for progesterone) for transported substrate in Mdr1 and a complicated mode of interactions between them.
Interaction of LDS-751 and rhodamine 123 with P-glycoprotein: evidence for simultaneous binding of both drugs.
TLDR
The interaction of the transporter with LDS-751 and rhodamine 123, both of which are believed to bind to the putative R-site, is characterized, concluding that the two-site drug binding model for P-glycoprotein requires modification.
Transition State Analysis of the Coupling of Drug Transport to ATP Hydrolysis by P-glycoprotein*
TLDR
It is concluded that basal ATPase activity associated with Pgp is not a consequence of transport of an endogenous lipid or other endogenous substrates, rather, it is an intrinsic mechanistic property of the enzyme.
Rapid Identification of P-glycoprotein Substrates and Inhibitors
TLDR
The successful application of pharmacophore models to accurately predict P-gp binding is shown, which holds promise to anticipate drug-drug interactions from screening drug databases and a priori prediction of novel P- gp inhibitors or substrates.
Active transport of fluorescent P-glycoprotein substrates: evaluation as markers and interaction with inhibitors.
TLDR
Results support the assertion of two unequal substrate binding sites that are allosterically dependent on each other on P-gp, and suggest that either DNR or LDS is generally the fluorescent substrate most responsive to inhibition, there may be other substrates yet even more sensitive.
Correlation between Steady-state ATP Hydrolysis and Vanadate-induced ADP Trapping in Human P-glycoprotein
TLDR
It is suggested that substrates modulate the rate of ATPase activity of Pgp by controlling the rateof dissociation of ADP following ATP hydrolysis and that ADP release is the rate-limiting step in the normal catalytic cycle of PGP.
Rhodamine inhibitors of P-glycoprotein: an amide/thioamide "switch" for ATPase activity.
TLDR
In MDCKII-MDR1 cells, the tertiary thioamide- containing derivatives promote uptake of calcein AM and have very slow passive, absorptive, and secretory rates of transport relative to transport rates for tertiary amide-containing derivatives.
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Competition of Hydrophobic Peptides, Cytotoxic Drugs, and Chemosensitizers on a Common P-glycoprotein Pharmacophore as Revealed by Its ATPase Activity (*)
TLDR
It is concluded that the various MDR type substrates and chemosensitizers compete on a common drug binding site present in Pgp, similar to classical Michaelis-Menten competition.
P-glycoprotein Is Stably Inhibited by Vanadate-induced Trapping of Nucleotide at a Single Catalytic Site (*)
TLDR
The finding that vanadate trapping of nucleotide at just one site/Pgp is sufficient to give full inhibition of ATPase activity shows that the two predicted nucleotide sites can not function independently as catalytic sites.
The multidrug-resistance-reverser verapamil interferes with cellular P-glycoprotein-mediated pumping of daunorubicin as a non-competing substrate.
TLDR
Evidence is obtained that verapamil is actively transported by the MDR-related P-glycoprotein and that verAPamil and daunorubicin are non-competing substrates for P- glycoprotein.
Mutation of glycine 185 to valine alters the ATPase function of the human P-glycoprotein expressed in Sf9 cells.
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TLDR
Kinetic analyses indicate that cyclosporin A, an inhibitor of Pgp, binds to the verapamil and vinblastine binding/transport site(s) in the Pgp.
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TLDR
The data show that a low-dose multidrug approach to saturation reversal of theMultidrug pump is feasible in cell culture and provides the initial experimental basis for the development of an effective regime of such combination reversal therapy.
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