Sodium Iodide Symporter (NIS) is a promiscuous secondary transporter which binds and translocates sodium cations along with a number of monovalent inorganic anions of different size and geometry. Remarkably, the transport can be either electrogenic (Na+:anion = 2:1) or electroneutral (Na+:anion = 1:1), depending on the anion. In the thyroid gland, NIS is involved in the transport of 1 I- and 2 Na+ ions through the membrane of the thyrocytes and is critical for the synthesis of the thyroid hormones. In addition, the development of gene targetting techniques that allow for NIS expression in cancer cells via viral vectors opens the possibility for cancer imaging and treatment through translocation of radiotracer anions such as the spherical monoatomic 125I-, and the tetrahedral polyatomic 99TcO4- and 18BF4-, which are among the NIS substrates. Unfortunately, due to lack of crystal structures, little is known about the 3D organization of NIS and how it relates to anion binding and transport. This impedes the development of mutants of NIS with practical application in cancer imaging and treatment. Analysis of protein motifs involved in anion binding in existing crystal structures in the PDB database may shed light on the structural requirements for anion coordination in NIS and may be used to guide mutation and radiotracer uptake studies. Multiscale computer simulations of the anions in water, in contact with small biomimetic compounds and within the protein active sites can complement further the structural determinants with relevant thermodynamic data. Here we present the results of a scan of the PDB database for proteins involved in binding with the panel of monovalent anions transported by NIS, which reveals their most common coordination numbers, coordination sphere geometries, and preferred binding protein groups and residues. Quantum mechanics, molecular dynamics and free energy of perturbation calculations for the anions in the presence of water, small molecules resembling the protein environment, or the full protein active site have been done as well for elucidation of the energetics of binding. Our findings have been put in the context of anion coordination to the hypothesized binding sites of NIS and the experimentally observed different transport stoichiometries.

Protein determinants of anion binding: Application to sodium iodide symporter

255th National Meeting (2018)

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