Structural insights into the mechanism of the sodium/iodide symporter

The sodium/iodide symporter (NIS) is the essential plasma membrane protein that mediates active iodide (I^-) transport into the thyroid gland, the first step in the biosynthesis of the thyroid hormones-the master regulators of intermediary metabolism. NIS couples the inward translocation of I^- against its electrochemical gradient to the inward transport of Na⁺ down its electrochemical gradient^1,2. For nearly 50 years before its molecular identification³, NIS was the molecule at the centre of the single most effective internal radiation cancer therapy: radioiodide (¹³¹I^-) treatment for thyroid cancer². Mutations in NIS cause congenital hypothyroidism, which must be treated immediately after birth to prevent stunted growth and cognitive deficiency². Here we report three structures of rat NIS, determined by single-particle cryo-electron microscopy: one with no substrates bound; one with two Na⁺ and one I^- bound; and one with one Na⁺ and the oxyanion perrhenate bound. Structural analyses, functional characterization and computational studies show the substrate-binding sites and key residues for transport activity. Our results yield insights into how NIS selects, couples and translocates anions-thereby establishing a framework for understanding NIS function-and how it transports different substrates with different stoichiometries and releases substrates from its substrate-binding cavity into the cytosol.