Internal duplication and homology with bacterial transport proteins in the mdr1 (P-glycoprotein) gene from multidrug-resistant human cells

Abstract

Resistance of tumor cells to multiple cytotoxic drugs is a major impediment to cancer chemotherapy. Multidrug resistance in human cells is determined by the mdr1 gene, encoding a high molecular weight membrane glycoprotein (P-glycoprotein). Complete primary structure of human P-glycoprotein has been determined from the cDNA sequence. The protein, 1280 amino acids long, consists of two homologous parts of approximately equal length. Each half of the protein includes a hydrophobic region with six predicted transmembrane segments and a hydrophilic region. The hydrophilic regions share homology with peripheral membrane components of bacterial active transport systems and include potential nucleotide-binding sites. These results are consistent with a function for P-glycoprotein as an energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.