Bacterial multidrug resistance (MDR) is a growing health problem that is a major challenge in the treatment of most infectious diseases. MDR is caused by the up-regulation of MDR efflux pumps that are imbedded in the cell membranes of bacteria. An important class of MDR pumps is the Multi Antimicrobial Toxin Extrusion (MATE) transporters from the Multidrug/Oligosaccharidyl-lipid/Polysaccharide (MOP) Super Family. MATE transporters translocate various hydrophobic substrates, such as norfloxacin by coupling them to either Na+ or H+ gradients. Our goal is ascertain the structural components that are involved in the translocation of drug molecules through the lipid bilayer by MATE transporters and to understand how these efflux pumps achieve their wide range of drug specificities. An important long-term objective is to provide a detailed structural framework for comprehending the general transport mechanisms that confer the MDR phenotype. A high-resolution atomic structure of a bacterial MATE transporter will also serve as an excellent model for other important secondary transporters that are involved in the translocation of sugars, amino acids, and ions. An x-ray structure of bacterial MATE transporters will also provide a structural basis for the translocation of substrate by homologous mammalian MOP transporters. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM070480-01A1
Application #
6867207
Study Section
Biophysical Chemistry Study Section (BBCB)
Program Officer
Chin, Jean
Project Start
2005-02-01
Project End
2009-01-31
Budget Start
2005-02-01
Budget End
2006-01-31
Support Year
1
Fiscal Year
2005
Total Cost
$353,210
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
He, Xiao; Szewczyk, Paul; Karyakin, Andrey et al. (2010) Structure of a cation-bound multidrug and toxic compound extrusion transporter. Nature 467:991-4