Major photoaffinity drug labeling sites for iodoaryl azidoprazosin in P-glycoprotein are within, or immediately C-terminal to, transmembrane domains 6 and 12.
P-glycoprotein can mediate multidrug resistance in tumor cells and is hypothesized to be an energy-dependent drug efflux pump. The protein is composed of two cassettes; each cassette contains six transmembrane domains followed by a nucleotide binding fold. The [125I]iodoaryl azidoprazosin photoaffinity drug binding sites in P-glycoprotein have been mapped by immunological analysis. After complete digestion of P-glycoprotein with trypsin, two major photolabeled fragments have been mapped. The 5- and 4-kDa fragments are located within, or immediately C-terminal to, the last transmembrane domain of each cassette: transmembranes 6 and 12 of P-glycoprotein, respectively. The 4-kDa fragment maximally extends up to, but not including, the Walker A motif of the second nucleotide binding fold, whereas the 5-kDa fragment maximally extends a few residues beyond the Walker A motif of the first nucleotide binding fold. A minor photolabeling domain is also found between transmembrane domain 4 and up to, but not including, transmembrane domain 6. These data suggest that a portion of the drug binding site in P-glycoprotein is in close proximity to ATP binding regions. Furthermore, symmetrical regions in each cassette of P-glycoprotein are likely to participate in drug efflux.[1]References
- Major photoaffinity drug labeling sites for iodoaryl azidoprazosin in P-glycoprotein are within, or immediately C-terminal to, transmembrane domains 6 and 12. Greenberger, L.M. J. Biol. Chem. (1993) [Pubmed]
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