(ABC) superfamily, and genetic defects in human homologs are responsible for several human diseases including cystic fibrosis, hyperinsulinemia and macular dystrophy. The maltose system is well-characterized both genetically and biochemically and provides an ideal model system to study the structure and function of an ABC transporter. Our laboratory uses a combination of molecular, biochemical and biophysical methods to study the mechanism of action of this transporter. As illustrated in the figure, a periplasmic maltose binding-protein (MBP) binds the sugar maltose with high affinity and directs it to a membrane-associated transport complex containing MalF, MalG and two copies of MalK (MalFGK2). Interaction of maltose-MBP with the transport complex activates the ATPase activity of the MalK subunit(s) via a transmembrane signaling event, perhaps by bringing together the two MalK subunits to complete the nucleotide-binding site(s). We recently discovered that MBP becomes tightly bound to the transport complex in the catalytic transition state in a conformation that displays a low affinity for maltose so that maltose is transferred to MalFGK2 each time ATP is hydrolyzed. In the next few years, we will take full advantage of new data obtained from the crystal structure of the MalK subunit to probe the conformational changes associated with the transport cycle and to understand why two ATP-binding sites are required for transport to occur. We are currently using fluorescence and electron spin resonance to monitor conformational changes at specific sites in the transport complex. We are also involved in collaborative efforts to obtain, for the first time, a high resolution structure of a complete ABC transporter.

Education

Selected Publications

• Khare D.;Oldham, M. L.;Orelle, C.;Davidson, A. L.;Chen, J., Alternating Access in Maltose Transporter Mediated by Rigid-Body Rotations . Molecular Cell 2009 , 33 , 528-536.
• Oldham M. L.;Davidson, A. L.;Chen, J., Structural insights into ABC transporter mechanism . Current Opinion in Structural Biology 2008 , 18 , 726-733.
• Davidson A. L.;Dassa, E.;Orelle, C.;Chen, J., Structure, function, and evolution of bacterial ATP-binding cassette systems . Microbiology and Molecular Biology Revie 2008 , 72 , 317-364.
• Rajagopalan L.;Greeson, J. N.;Xia, A.;Liu, H.;Sturm, A.;Raphael, R. M.;Davidson, A. L.;Oghalai, J. S.;Pereira, F. A.;Brownell, W. E., Tuning of the outer hair cell motor by membrane cholesterol . Journal of Biological Chemistry 2007 , 282 , 36659-36670.