The structure of the Ala-109-->Thr mutation of human
transthyretin, a nonamyloidogenic variant with enhanced
thyroxine binding, has been determined by x-ray diffraction to a resolution of 1.7 A. The model, including 175
solvent water molecules, has been refined by constrained least squares to an R-value of 0.157. The standard deviations for
protein geometry are 0.016 A for bond distances, 0.5 degree for bond angles, 0.031 A for 1-4 distances, and 0.005 A for deviations of planar groups from their least squares plane. The estimated error in
protein atomic coordinates is 0.12 A. Residue 109 extends inward between the two beta sheets which form the major component of the monomer, as does the side chain of residue 30 in the amyloidogenic Met-30 variant. Comparison of the Thr-109 structure with that of the normal shows that the extra atoms of the
threonine fit into empty space between sheets and make no extensive changes to the molecular conformation. The substitution at 109 causes small local changes in the secondary structure of the A, G, and H strands resulting in a shift of residues 15-17, 108-110, and 117 in each monomer. The
thyroxine-binding sites of the Thr-109 and Met-30 variants and of the normal
protein are compared, and the results suggest that the variation in affinity for
thyroxine between the three
proteins may arise from differences in the size of the binding pocket.