X-ray crystal structure of the Ala-109-->Thr variant of human transthyretin which produces euthyroid hyperthyroxinemia.
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.
Steinrauf
L K
LK
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis 46202-5122.
Hamilton
J A
JA
Braden
B C
BC
Murrell
J R
JR
Benson
M D
MD
D001665:Binding Sites; D003461:Crystallography; D006801:Humans; D006981:Hyperthyroxinemia / Q000097:blood; D066298:In Vitro Techniques; D008958:Models, Molecular; D011228:Prealbumin / Q000737:chemistry / Q000648:ultrastructure*; D011994:Recombinant Proteins / Q000737:chemistry; D013329:Structure-Activity Relationship; D013974:Thyroxine / Q000378:metabolism; D014961:X-Ray Diffraction
D011228:Prealbumin; D011994:Recombinant Proteins; D013974:Thyroxine