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Transthyretin (TTR, formely called prealbumin), one of the transporters of the hormone thyroxine, and retinol-binding protein (RBP), the specific carrier of retinol (vitamin A), form a complex under physiological conditions that prevents the glomerular filtration of the low molecular size RBP (21,000 daltons) in the kidneys (1). The complex can form in vitro between RBP and TTR from different species, including those species that are distant in evolution (2). We prepared crystals from complexes containing human TTR and chicken RBP (3). The dissociation constant of this complex (1.0 X 10 sup -7 M) is similar to those of the complexes of human RBP with human TTR (1.1 X 10 sup -7 to 1.5 X 10 sup -7 M) and of chicken RBP with chicken TTR (1.1 x 10 sup -7 to 1.6 x 10 sup -7 M) (4).
The crystallographic data of this complex are presented in Table 1.(Table 1 omitted) The structure of the complex was solved with the molecular replacement method (5) with one of the human TTR coordinate sets (6) and coordinates of bovine holo-RBP (7). The final model statistics (8) are an R factor of 20.1 (R factor = Sigma F sub o -F sub c Sigma FF sub o where F sub o is the observed and F sub c the calculated structure factor) with root-mean-square deviations in the bonds of 0.018 Angstrom, in the angles of 3.7deg, and in the dihedrals of 26.7deg.
The three-dimensional structure of human (9, 10) and bovine (7) holo-and apo-RBP, of wild-type (II) and several mutant human TTRs (12, 13), and of complexes of wild-type TTR with several pharmacologically important compounds (6, 14) are all known, TTR is a tetramer of four identical subunits, each 127 amino acids long (Fig. 1) (11).(Fig. 1 omitted) The monomers are organized into two extensive beta sheets, each composed of four strands that are all antiparallel, with one exception (11). Two monomers form a stable dimer by the extension of their two beta sheets through hydrogen bonding that involves the four strands (two from each monomer) at the edges of the two subunits. The two dimers of the tetramer are separated by a channel and in contact through symmetry related loops. The channel, approximately 10 Angstrom in diameter,...