Open AccessCo‐operating ATP sites in the multiple drug resistance transporter Mdr1
Author(s) -
Buxbaum Engelbert
Publication year - 1999
Publication title -
european journal of biochemistry
Language(s) - English
Resource type - Journals
eISSN - 1432-1033
pISSN - 0014-2956
DOI - 10.1046/j.1432-1327.1999.00643.x
Subject(s) - atp hydrolysis , verapamil , transporter , atp binding cassette transporter , atpase , chemistry , p glycoprotein , adenosine triphosphate , efflux , inhibitory postsynaptic potential , atp synthase , biochemistry , enzyme , biophysics , pharmacology , multiple drug resistance , calcium , biology , gene , endocrinology , organic chemistry , antibiotics
The ATPase activity of the multiple drug resistance transporter Mdr1 (P‐glycoprotein, gp170) depended on the concentration of ATP with both positive and negative co‐operativity both in the absence and in the presence of verapamil. Four co‐operating binding sites for ATP were required to adequately model the experimental findings. The activation energy for the ATPase activity increased from ≈ 385 kJ·mol −1 at 10 µ m ATP to 512 kJ·mol −1 at 1600 µ m , while changes in verapamil concentration had little effect. This indicates that the reaction mechanism of ATP hydrolysis depends on ATP concentration and is further evidence for co‐operation of ATP binding sites. Free ATP in higher concentration was inhibitory; however, this inhibition could be reduced by complexing the ATP with Mg 2+ . Free Mg 2+ had little effect on Mdr1 apart from complexing ATP.