This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Bacterial multidrug resistance (mdr) presents a serious health risk as an increasing number of human pathogens are showing resistance to currently available treatments. One mechanism of mdr involves export of toxic compounds from the cell by multidrug efflux transporters. These membrane proteins have been shown to bind to and efflux a diverse array of structurally and chemically dissimilar compounds. The molecular details of how these transporters recognize and expunge drugs is not fully understood, in part due to the difficulty associated with purifying and crystallizing intrinsic membrane proteins. However, a growing number of proteins have been identified that regulate the expression of multidrug transporters in response to the same toxic compounds that the transporters extrude. These transcriptional regulators are much more amenable to structural and biochemical studies as they are soluble, cytosolic proteins which can be purified more easily and in the quantities that are necessary for structural and biochemical studies. One such transcriptional regulator from Bacillus subtilis, BmrR (bacterial multidrug resistance regulator), activates transcription of the bmr multidrug transporter gene by binding to a plethora of structurally dissimilar lipophilic cationic compounds, many of which are substrates of Bmr. In the absence of drug, BmrR remains bound to the bmr promoter and functions as an anti-activator. Structural studies of BmrR-DNA bound to different inducer molecules along with structures of multidrug binding pocket mutants will help to elucidate the principles by which BmrR can recognize multiple structurally dissimilar drugs.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Biotechnology Resource Grants (P41)
Project #
5P41RR001209-28
Application #
7598321
Study Section
Special Emphasis Panel (ZRG1-BPC-E (40))
Project Start
2007-03-01
Project End
2008-02-29
Budget Start
2007-03-01
Budget End
2008-02-29
Support Year
28
Fiscal Year
2007
Total Cost
$398
Indirect Cost
Name
Stanford University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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