Modeling the Tripartite Drug Efflux Pump Archetype: Structural and Functional Studies of the Macromolecular Constituents Reveal More Than Their Names Imply.

It is a remarkable age in molecular biology when one can argue that our current understanding of a process is influenced as much by structural studies as it is by genetic and physiological manipulations. This statement is particularly poignant with membrane proteins for which structural knowledge has been long impeded by the inability to easily obtain crystal structures in a lipid matrix. Thus, several highresolution structures of the components comprising tripartite multidrug efflux pumps from Escherichia coli and Pseudomonas aeruginosa are now available and were received with much acclaim over ever-evolving crystal structures of soluble, aqueous proteins. These structures, in conjunction with functional mutagenesis studies, have provided insight into substrate capture and binding domains and redefined the potential interactions between individual pump constituents. However, correct assembly of the components is still a matter of debate as is the functional contribution of each to the translocation of drug substrates over long distances spanning the Gram-negative cell envelope.