Molecular Conformation of Thyroid Hormones: Structure and Binding Interactions of Thyroxine

Abstract

In an accurately determined X-ray diffraction study of the thyroid hormone thyroxine (T₄), the two independent conformations in the crystal lattice show significant differences in the outer phenyl ring geometry when compared with that of 3,5,3′-triiodothyronine (T3). The major differences between the T₄ and T₃ structures are a shortened C4′-04′ bond, contraction of the C3′-C4′-C5′ angle and an increase in the C3′ and C5′ angles of Tit. These changes can be correlated with the difference in acidity of the 4′-OH of T₄ and T₃ and help to explain binding affinity differences among thyroactive compounds. The hydrogen bond directionality observed in T₄ and other thyroid structures offers an insight into the molecular details of the hormone-receptor site. The conformation of one T₄ molecule is cisoid, that of the other transoid, the first such instance of different overall conformations to be found in the same crystal lattice. One T₄ molecule has the side chain nearly coplanar with the inner ring, an unusual conformation among thyroid structures.