Molecular complexes of thyroid hormone tyrosyl rings with aromatic donors. Possible relationship to receptor protein interactions.

Abstract

Several lines of evidence have indicated that thyroid hormones share common molecular properties (accessible planar face and lateral halogenation) with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds of environmental importance and can modulate their toxicity. Binding of dioxin to a soluble intracellular protein (dioxin or Ah receptor) appears to be the initial step in their mechanism of toxicity and a stacking interaction model has been proposed at the molecular level. It has also been recognized that the Ah receptor and the triiodothyronine nuclear receptor share certain physical and chemical properties important in their binding interactions. In this work, we examined the possibility that thyroid hormones might also be able to bind by a stacking complexation mechanism. By use of methods based on nuclear magnetic resonance spectroscopy, selected, structurally distinct thyroid hormone analogues with widely different hormonal activities were shown to function as electron acceptors in molecular complexes with aromatic donors involving the nonphenolic or tyrosyl ring. Binding free energies for these complexes correlated well with those previously reported for the triiodothyronine (L-T3) nuclear receptor binding interaction with the same compounds. This included preference for L-T3 over thyroxine (L-T4), very favorable binding of 3,5,3'-triiodothyroacetic acid (Triac), and marked preference for L-T3 over D-T3. These results suggest that a considerable part of the structural specificity in thyroid hormone action may be mediated by the tyrosyl ring interaction. Binding ligands for the triiodothyronine nuclear receptor and the Ah receptor may share common molecular parameters in the expression of their binding activities.