The iodothyronine deiodinases (Dio) regulate thyroid hormone (TH) activity by removing iodine from the inner or outer rings of the series of iodinated thyronine substrates. Understanding the structure of this critical enzyme is important for developing treatments for thyroid hormone-related disorders. Our group has been investigating the structure and dynamics of these thioredoxin-fold proteins to determine how a flexible loop near the active site affects the substrate binding and specificity. Molecular dynamics simulations using AMBER and modified force fields are used on the apo and TH bound monomers and dimers of the catalytic regions of the three types of Dio. In the active dimer apo protein, asymmetry in the loop structures suggests a potential for allosteric regulation of protein activity. The topology of the active site region in the inactive monomer is compared to the dimer to determine how interactions at the dimerization interface affect specificity of substrate binding. Comparisons between the sequences of the three types of Dio may further tune specificity by modulating the access of thyroid hormones and xenobiotic antagonists and/or inhibitors.

Structure and dynamics of the thyroid hormone-activating and deactivating iodothyronine deiodinases

2019 Spring National Meeting

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