UNIVERSITY OF ARIZONA
The kidney and liver actively secrete many drugs from the body, and unwanted drug-drug interactions at the sites of secretion in these organs are a source of substantial morbidity and mortality. The rate-limiting step in the secretion of cationic drugs by the human liver and kidney involves the mediated exchange of organic cations (OCs) for hydrogen ion (H+), a transport process that, until recently, was undescribed at the molecular level. Recent work identified two transporters, MATE1 and MATE2-K, as these "OC/H+ exchangers." Although MATE proteins were heretofore unknown in mammals, the "Multidrug And Toxin Extruders" are a very large family of multidrug transporters in bacteria, fungi and plants. Despite their biological importance, and their clinical importance in humans, virtually nothing is known about the structure of these transporters, or of the influence of structure on MATE transport function. In this proposal we outline experiments to establish the secondary structure of human MATE transporters and identify specific sites within these proteins that influence drug binding. The results of these studies will help predict and, ideally, preempt unwanted drug-drug interactions in both the kidney and liver, and can be expected to assist in development of programs of rational drug design.