Structural mechanism for multidrug efflux systems

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Su, Chih-chia
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Edward W. Yu
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Biochemistry, Biophysics and Molecular Biology

The Department of Biochemistry, Biophysics, and Molecular Biology was founded to give students an understanding of life principles through the understanding of chemical and physical principles. Among these principles are frontiers of biotechnology such as metabolic networking, the structure of hormones and proteins, genomics, and the like.

The Department of Biochemistry and Biophysics was founded in 1959, and was administered by the College of Sciences and Humanities (later, College of Liberal Arts & Sciences). In 1979 it became co-administered by the Department of Agriculture (later, College of Agriculture and Life Sciences). In 1998 its name changed to the Department of Biochemistry, Biophysics, and Molecular Biology.

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  • Department of Biochemistry and Biophysics (1959–1998)

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Bacteria such as Escherichia coli, Campylobacter jejuni and Neisseria gonorrhoeae have developed various mechanisms to overcome toxic environments that are otherwise unfavorable for their survival. One important strategy that bacteria use to expel toxic compounds, including heavy metal ions, is the expression of membrane efflux transporters that recognize and actively export these toxic compounds out of bacterial cells, thereby allowing them to survive in extremely toxic conditions. Many of these transporters are multiple drug binding proteins which extrude different toxic chemicals and mediate a phenomenon of multidrug resistance (MDR) in bacteria. The expression of these efflux transporters is tightly controlled at the transcriptional level by transcriptional regulators. A number of these transcriptional regulators are also multidrug binding proteins, which recognize and respond to the same set of toxic chemicals that are expelled by the efflux transporters they regulate. The goal of this dissertation is to elucidate the structures and fundamental mechanisms that give rise to multiple drug recognition in these efflux transporters and their regulators. We have determined several x-ray structures of these important proteins, including the E. coli AcrB efflux transporter, C. jejuni CmeR transcriptional regulator and E. coli CusB heavy-metal efflux protein. We also crystallized the N. gonorrhoeae NorM multidrug transporter and collected the x-ray diffraction data of the crystals. To gain further insight into the mechanism of multiple drug recognition, we examined the binding affinities of AcrB and AcrR to different drugs using fluorescence polarization assays. In this thesis, we will summarize the new findings with AcrB, AcrR, CmeR and CusB, and discuss the structure and function of these efflux transporters and regulators.

Thu Jan 01 00:00:00 UTC 2009