Modulation of ATP and drug binding by monoclonal antibodies against P-glycoprotein

✍ Scribed by Elias Georges; Jian-Ting Zhang; Victor Ling

• Book ID: 102887046
• Publisher: John Wiley and Sons
• Year: 1991
• Tongue: English
• Weight: 719 KB
• Volume: 148
• Category: Article
• ISSN: 0021-9541
• DOI: 10.1002/jcp.1041480321

✦ Synopsis

The role of P-glycoprotein in mediating the drug-resistance phenotype in multidrug resistant cells is now well documented. It is thought to function as an energy-dependent drug-efflux pump of broad specificity. Structurally, P-glycoprotein is an internally duplicated molecule containing two large multi-spanning transmembrane domains and two cytoplasmic ATP binding domains. In this report we demonstrate that monoclonal antibodies C219, C494, and C32 directed against short linear regions of the P-glycoprotein molecule inhibit ATP binding to P-glycoprotein in vitro. We also provide direct evidence that both predicted ATP-binding domains bind ATP and that there is co-operativity between the two sites. In addition, the capacity of P-glycoprotein to bind the calcium channel blocker, azidopine, is inhibited differentially by the antibodies. These observations are the first evidence linking specific perturbations of the P-glycoprotein molecule with ATP and drug binding.