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The three-dimensional structure of the thyroid hormone metabolite,
3,3'-diiodo-L-thyronine (3,3'-T2), complex with human serum transthyretin (TTR)
has been refined to R = 18.5% for 8-2 A resolution data. This is the first
detailed description of a thyroid hormone metabolite binding to a thyroid
transport protein. The four TTR monomeric subunits form a tetramer in the same
manner as the native transthyretin reported earlier (Blake, C. C. F., Geisow, M.
J., Oatley, S. J., Rerat, B., and Rerat, C. (1978) J. Mol. Biol. 121, 339-356).
The two hormone binding sites of the TTR tetramer are occupied by 3,3'-T2. A
statistical disorder model for the ligand was applied with a 50% occupancy to
account for the discrepancy between the crystallographic 2-fold symmetry of the
binding sites and the lack of such symmetry for 3,3'-T2. The bound metabolite
has an overall transoid conformation with the either bridge intermediate between
skewed and perpendicular. The hormone metabolite is bound 3.5 A deeper and with
a different orientation in the channel than observed for thyroxine (T4), thereby
revealing the presence of another set of halogen binding sites close to the
center of the tetramer. When compared with the binding of T4, these data show
that the 3-iodine of 3,3'-T2 occupies the same site as the 3'-iodine of T4, and
the metabolite 3'-iodine occupies the water site observed in the T4 complex. The
binding affinity of 3,3'-T2, which is 100-fold lower than that of T4, reflects
the lack of the second pair of iodine atoms interacting in the channel. In order
to understand the tighter binding of T4 observed in the Ala-109----Thr mutant,
modeling studies were carried out that indicate that this modification could
shorten the contacts between thyroid hormone iodines and residues 108-110 of the
binding site.
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