Sharom F J
Guelph-Waterloo Centre for Graduate Work in Chemistry and Biochemistry, University of Guelph, Ontario, Canada.
J Membr Biol. 1997 Dec 1;160(3):161-75. doi: 10.1007/s002329900305.
Pgp is an atypical translocating ATPase, with low affinity for ATP and high constitutive ATPase activity. Pgp also has an unusually broad specificity for hydrophobic substrates, including many chemotherapeutic drugs. Transport studies in reconstituted systems indicate that drug transport requires ATP hydrolysis and is active, generating a drug concentration gradient. Binding of drugs and ATP to Pgp induces conformational changes in the protein, and the drug binding site is conformationally coupled to the NBDs. Evidence accumulated to date suggests that the transporter interacts directly with nonpolar substrates within the membrane environment, and may act as a drug flippase, moving drugs from the inner to the outer leaflet of the bilayer. Chemosensitizers that block the action of Pgp are proposed to act as alternative substrates, but their high rate of spontaneous flip-flop across the membrane results in futile cycling of the transporter.
Pgp是一种非典型的转运ATP酶，对ATP亲和力低，但组成型ATP酶活性高。Pgp对包括许多化疗药物在内的疏水性底物也具有异常广泛的特异性。在重组系统中的转运研究表明，药物转运需要ATP水解，是主动转运，会产生药物浓度梯度。药物和ATP与Pgp的结合会诱导蛋白质构象发生变化，并且药物结合位点在构象上与核苷结合域相偶联。迄今为止积累的证据表明，该转运体在膜环境中直接与非极性底物相互作用，可能充当药物翻转酶，将药物从双层膜的内膜小叶转运到外膜小叶。据推测，阻断Pgp作用的化学增敏剂可作为替代底物，但它们在膜上的自发翻转速率很高，导致转运体徒劳循环。
