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Multidrug Resistance Research
The emergence of resistance to multiple drugs is an obstacle in the treatment of bacterial, fungal infections and cancer. One of the mechanisms responsible for this phenomenon is the expulsion of a wide variety of unrelated cytotoxic drugs from the cell by dedicated membrane proteins referred to as multidrug transporters. It is critical to understand the structure and function of MDR transporters in order to design new and effective therapeutic drugs. One of the major classes of MDR transporters is secondary multi-drug resistant transporter that drives the efflux of drugs by an electrochemical proton gradient in an antiporter mechanism. These transporters belong to four subfamilies, of which small multidrug resistance (SMR) family seems to be the simplest from a molecular perspective. EmrE a secondary multidrug transporter from Escherichia coli belongs to SMR family and functions as a proton:drug antiporter. EmrE is mostly hydrophobic with a total of eight charged residues, and it is capable of recognizing a wide range of chemically unrelated substrates. The lab has several ongoing projects attempting to elucivate the structural basis of substrate recogntion and translocation for the bacterial lipid flippase MsbA, human multidrug resistance protein (p-glycoprotein) and the bacterial multidrug trasnporter EmrE.
 
Current Researchers
 
Ping
Ping Zou, Ph.D. Post Doctoral Fellow. I monitor the conformational alterations of MsbA upon Lipopolysaccharide (LPS) binding and following ATP turnover by electron paramagnetic resonance (EPR).
 
Smriti
Smriti, Ph.D. Post Doctoral Fellow. I am trying to identify the residues of MsbA that involve drug binding and transport. MsbA is a homolog of Pgp and belongs to a family of ATP-binding cassette (ABC) transporters. The proteins of this family are of great medical interest since over expression of these proteins causes multidrug resistance in the cells, mutations in the genes encoding these proteins results in diseases like cystic fibrosis, tangier disease and adrenoleukodystrophy.
 
 
Recent Publications
 
Borbat PP, Surendhran K, Bortolus M, Zou P, Freed JH, Mchaourab HS. Conformational Motion of the ABC Transporter MsbA Induced by ATP Hydrolysis. PLoS Biol. 2007 Oct 9;5(10):e271. PMID: 17927448
 

Dong J, Yang G, Mchaourab HS. Structural basis of energy transduction in the transport cycle of MsbA. Science. 2005 May 13;308(5724):1023-8.

 
 
 
 
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