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Diss. (sammanfattning) Uppsala : Universitet, 2005. / Härtill 4 uppsatser.

Thesis (Ph. D.)--Georgia State University, 2008. / Title from file title page. Dabney W. Dixon, committee chair; Kathryn B. Grant, Jerry Smith, committee members. Electronic text (171 p. ; ill. (some col.)) : digital, PDF file. Description based on contents viewed June 23, 2008. Includes bibliographical references.

The emergence of multidrug resistance is a serious medical problem that has significantly affected the treatment of tumor cells and infectious diseases. This multidrug resistance phenotype is mediated by the action of a large family of membrane proteins that act as active transporters or energy driven efflux pumps in both of prokaryotic and eukaryotic cells. Most eukaryotic multidrug efflux pumps belong to the ATP binding cassette (ABC) family of transport proteins that include P-glycoprotein (P-gp1), Multidrug Resistance Associated Protein (MRP1), and Breast Cancer Resistance Protein (BCRP). In prokaryotic cells, Lactococcus lactis LmrA, a homolog of P-gp1, mediates drug resistance to antibiotics and cytotoxic drugs. The transport function of these proteins is facilitated by the hydrolysis of ATP. However, the mechanism by which these proteins bind to, and are able to transport structurally dissimilar drugs across the cell membrane remains poorly understood. In this thesis we have attempted to characterize the interactions of various ABC transporters (MRP1, BCRP, and LmrA) with structurally diverse drugs, using a well characterized photoreactive drug analogue of Rhodamine 123, [125I] iodoaryl azido-rhodamine 123 (IAARh123). In the case of MRP1 interaction with Rhodamine 123, it was of interest to determine the nature of MRP1 drug interactions. In that study, our results show that CHAPS (1-[(3-cholamidopropyl) dimethylamino]-1-propansulfate) and Brij35 inhibited the photolabeling of MRP1 with IAARh123, and this interaction occurred outside the lipid bilayer. These results were unexpected in light of previous results with another ABC transporter which also binds to Rhodamine 123. Consequently, we show that non-toxic concentrations of CHAPS and Brij35 potentiate the toxicity of two MRP1 substrates, vincristine and etoposide (VP16). In the second chapter, we have used IAARh123 to demonstrate for the first time that the BCRP mediates drug resi

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by Wen-Liang Zhou. / Thesis (Ph.D.)--Chinese University of Hong Kong, 1996. / Includes bibliographical references (p. 125-144). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web.

The Escherichia coli vitamin B12 transporter BtuCD-F is a type II importer belonging to the ABC transporter superfamily. Available data suggest both exporters and type I importers in the ABC superfamily employ similar transport mechanism in which the transmembrane (TMDs) are open to cytoplasm in the resting state, and ATP binding induces a major conformational change resulting in opening of the TMDs instead to the periplasm. However, the crystal structures of BtuCD from E. coli and recent EPR spectroscopy studies indicate that this type II importer employs a substantially different mechanism in which the TMDs are open to the periplasm in the resting state and to the cytoplasm after ATP binding. We have developed robust methods to study the conformation and transport mechanism of BtuCD-F reconstituted into lipid bilayers using single molecule fluorescence resonance energy transfer (smFRET) measurements. Fluorescent probes have been introduced at a variety of diagnostic sites, enabling smFRET to be used to measure distance changes in different conformational states as well as to observe the transitions between these states in real time. These data suggest that thermal fluctuations enable the transporter to explore different functional conformational states in the absence of ATP or other ligands. They also suggest that the ATP-bound state is indeed open to the cytoplasm and ATP binding/hydrolysis increases the rate of transition between open and closed states. Efforts are currently underway to observe the transport of vitamin B12 through a single BtuCD-F oligomer in real-time.