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

Elias Georges, Jian‐Ting ‐T Zhang, Victor Ling

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)479-484
Number of pages6
JournalJournal of cellular physiology
Volume148
Issue number3
DOIs
StatePublished - Sep 1991

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ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Cell Biology

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