Thyroxine binding to type III iodothyronine deiodinase

Area of Science:

• Biochemistry
• Structural Biology
• Endocrinology

Background:

• Iodothyronine deiodinases (Dios) are crucial selenoproteins regulating active thyroid hormone (TH) levels.
• Type III deiodinase (Dio3) specifically deactivates TH by inner ring cleavage, a process involving a selenocysteine (Sec) residue.

Purpose of the Study:

• To elucidate the structural dynamics and mechanism of Type III iodothyronine deiodinase (Dio3).
• To understand how Dio3 achieves regioselective deiodination of thyroid hormones.

Main Methods:

• X-ray crystallography of a truncated Dio3 monomer.
• Multi-microsecond molecular dynamics simulations of the Dio3 thioredoxin-fold domain.
• Analysis of protein-ligand interactions, including halogen bonding.

Main Results:

• The unstructured Ω-loop dynamics are influenced by Trp207 interactions with solvent.
• A conserved Glu200 residue anchors the loop to the active site.
• A cryptic pocket accommodates thyroxine (T4) via I⋯Se and I⋯O halogen bonds, explaining Dio3's inner ring deiodination specificity.
• Dio3-type specific loop conformations, involving residues like Asp211, contribute to regioselectivity.

Conclusions:

• Dio3's structure and dynamics, particularly the Ω-loop, are key to its function in thyroid hormone metabolism.
• Halogen bonding interactions and type-specific loop conformations dictate Dio3's substrate selectivity.
• The proposed catalytic mechanism involves Cys168 attacking a selenenyl iodide intermediate.