Structural characterization of human urea transporters UT-A and UT-B and their inhibition
Gamma Chi, Larissa Dietz, Haiping Tang, M. Snee, Andreea Scacioc, Dong Wang, G. McKinley, Shubhashish Mukhopadhyay, A.C.W. Pike, R. Chalk, N. Burgess-Brown, Jean‐Pierre Timmermans, Wouter Van Putte, Carol V. Robinson, Katharina L. Dürr
Abstract
In this study, we present the structures of human urea transporters UT-A and UT-B to characterize them at molecular level and to detail the mechanism of UT-B inhibition by its selective inhibitor, UTB inh -14. High-resolution structures of both transporters establish the structural basis for the inhibitor’s selectivity to UT-B, and the identification of multiple binding sites for the inhibitor will aid with the development of drug lead molecules targeting both transporters. Our study also discovers phospholipids associating with the urea transporters by combining structural observations, native MS, and lipidomics analysis. These insights improve our understanding of urea transporter function at a molecular level and provide a blueprint for a structure-guided design of therapeutics targeting these transporters.