An atomic detail model for the human ATP binding cassette transporter P‐glycoprotein derived from disulphide cross‐ linking and homology modeling

Abstract

SPECIFIC AIMSThe crystal structures of two prokaryotic ATP binding cassette (ABC) transporters, MsbA and BtuCD, have recently been solved but they differ in their tertiary structure and domain interfaces. We have produced an atomic scale model of the paradigm human ABC transporter, the multidrug resistance P-glycoprotein (P-gp), based on a combination of the available structural data and novel chemical cross-linking data to determine the interface between the two transmembrane domains.PRINCIPAL FINDINGSP-gp is comprised of four domains: two transmembrane domains (TMDs), which contain the drug binding sites and define the translocation pathway across the membrane; and two cytoplasmic nucleotide binding domains (NBDs), which couple the energy associated with ATP binding and hydrolysis to drug transport. P-gp is the best-characterized human ABC transporter in terms of catalytic and transport function, and a detailed structure for P-gp would be a significant advance in elucidating a molecular mechanism for su...