Characterization of the Sodium Iodide Symporter Binding Sites

Abstract

Sodium iodide symporter (NIS) is a membrane protein responsible for accumulation of iodide (I-) in the thyroid and other organs. This is accomplished through active transports in which the sodium (Na+) gradient provides the driving force. In our approach we attempt to bring together the most recent finding on the NIS homologous systems and shine light on current and future application of NIS in clinical treatment of thyroid cancer. Furthermore we discuss our findings on NIS structure/function properties. The stoichiometry of the transport event has been elusive and intensely debated. In our approach we started with homology modeling to develop the NIS model. The structure was based on the x-ray structure of Vibrio parahaemolyticus sodium/galactose symporter (vSGLT), a close structural homologue exhibiting the same topological fold. Based on the topological identity we also used the x-ray structure of Aquifex aeolicus leucine transporter (LeuT) to further improve the model of our system. Sequence alignment was performed to identify important residues and potential substrate/ion binding sites. Radioactive labeled biomarkers were used as potential substrates/inhibitors, in line with the clinical applications. Aside from the radio-labeled iodide, we considered tetrafluoroborate, perchlorate, bromide, and thiocyanate. Firstly, the binding sites were identified through a docking process. Following which in order to enhance I- and inhibitor transport, necessary for improved imaging, we had to expand our system beyond the wild-type protein. The mutants we considered are all essential for transport and they are Q72N, I147C, E368A, and M68A. By inducing different rates of transport we can deduce how the protein responds to specific mutants. We have successfully identified a favorable response to our mutations and we are hopeful our approach to the engineered NIS protein will further aid in the treatment and imaging of thyroidal and extrathyroidal cancers.