Iodothyronine deiodinases (Dios) are important selenoproteins that control the concentration of the active thyroid hormone (TH) triiodothyronine through regioselective deiodination. The X-ray structure of a truncated monomer of Type III Dio (Dio3), which deiodinates TH inner rings through a selenocysteine (Sec) residue, revealed a thioredoxin-fold catalytic domain supplemented with an unstructured Ω-loop. Loop dynamics are driven by interactions of the conserved Trp207 with solvent in multi-microsecond molecular dynamics simulations of the Dio3 thioredoxin(Trx)-fold domain. Hydrogen bonding interactions of Glu200 with residues conserved across the Dio family anchor the loop's N-terminus to the active site Ser-Cys-Thr-Sec sequence. A key long-lived loop conformation coincides with the opening of a cryptic pocket that accommodates thyroxine (T4) through an I…Se halogen bond to Sec170 and the amino acid group with a polar cleft. The Dio3-T4 complex is stabilized by an I…O halogen bond between an outer ring iodine and Asp211, consistent with Dio3 selectivity for inner ring deiodination. Non-conservation of residues, such as Asp211, in other Dio types in the flexible portion of the loop sequence suggests a mechanism for regioselectivity through Dio type-specific loop conformations. Cys168 is proposed to attack the selenenyl iodide intermediate to regenerate Dio3 based upon structural comparison with related Trx-fold proteins.
Original Publication Citation
Bayse, C. A., Marsan, E. S., Garcia, J. R., & Tran-Thompson, A. T. (2020). Thyroxine binding to type III iodothyronine deiodinase. Scientific reports, 10, 1-10, Article 15401. https://doi.org/10.1038/s41598-020-72243-9
Bayse, Craig A.; Marsan, Eric S.; Garcia, Jenna R.; and Tran-Thompson, Alexis T., "Thyroxine Binding to Type III Iodothyronine Deiodinase" (2020). Chemistry & Biochemistry Faculty Publications. 192.