I study the conformational changes that underlie transport in membrane transporters belonging to the multidrug and toxic compound extrusion (MATE) family of transporters. These transporters couple the efflux of drug to an ion gradient and allows the cell sufficient time to adapt mechanisms to modify or degrade the drug or to modify the target of the drug. These mechanisms contribute to multidrug resistance in pathogens, a serious and growing public health threat, which is exacerbated by the dearth of new antibiotic treatments.
I am interested in determining the different conformations of the transporter during the transport cycle, which will enable me to propose a model of transport based on structural dynamics. To determine conformational changes, I will use double electron electron resonance (DEER) spectroscopy to observe the movement of transmembrane helices of the transporter in response to drug binding and changes in ion concentration. Additionally, global conformational changes will be correlated with local changes in structure upon substrate binding, protonation, and substrate release via changes in spin label mobility and solvent accessibility. The results of this research will identify previously unobserved intermediates of MATE transporters and may guide the development of novel therapeutic treatments that can be used in combination with existing therapies to counter drug resistance mechanisms in pathogens.
Hassane Mcharourab, PhD
University of Miami, Coral Gables, FL