Journal
SCIENTIFIC REPORTS
Volume 10, Issue 1, Pages -Publisher
NATURE RESEARCH
DOI: 10.1038/s41598-020-72243-9
Keywords
-
Categories
Funding
- National Institutes of Health [R15 GM119063-01A1]
Ask authors/readers for more resources
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 Omega -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 (T-4) through an ISe halogen bond to Sec170 and the amino acid group with a polar cleft. The Dio3-T-4 complex is stabilized by an IO 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available