The X-ray crystal structure refinements of normal human transthyretin and the amyloidogenic Val-30 → Met variant to 1.7-Å resolution

Jean A. Hamilton, Larry K. Steinrauf, Bradford C. Braden, Juris Liepnieks, Merrill Benson, Gosta Holmgren, Ola Sandgren, Lars Steen

Research output: Contribution to journalArticle

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Abstract

The x-ray crystal structures of normal human transthyretin (prealbumin) and the amyloidogenic Val-30-Met variant have been refined at 1.7-Å resolution to R-values of 0.168 and 0.179, respectively, for 19,882 and 20,362 reflections (Fobs > 2.0σ). Standard deviations for stereochemical parameters are 0.018 and 0.022 Å for bond distances, 0.030 and 0.038 Å for angle distances, and 0.035 and 0.070 Å for planar 1-4 distances. The newly refined normal structure shows improvement over the original structure of Blake and Swan (Blake, C. C. F., and Swan I. D. A. (1971) J. Mol. Biol. 61, 217-224) in stereochemistry and in the conformation of the loop regions. Residues Arg-103, Thr-123, Asn-124, and Pro-125 have now been resolved, and residues 1-9 and 126-127 have been modeled with the aid of simulated annealing refinement. The functional form of transthyretin is a tetramer, having a cylindrical cavity which will bind thyroxine and an exterior binding site for the complex of retinol with retinol-bindingprotein. The monomer is a β barrel flattened to become more like a sandwich with residue 30 in the interior. The methionyl for valyl substitution forces the β sheets of the monomer as much as 1 Å apart, resulting in a distortion of the thyroxine-binding cavity, in agreement with the independent observations that the Met-30 variant has low affinity for thyroxine.

Original languageEnglish
Pages (from-to)2416-2424
Number of pages9
JournalJournal of Biological Chemistry
Volume268
Issue number4
StatePublished - Feb 5 1993

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Prealbumin
Thyroxine
Crystal structure
X-Rays
Vitamin A
X rays
Monomers
Stereochemistry
Simulated annealing
Conformations
Substitution reactions
Binding Sites

ASJC Scopus subject areas

  • Biochemistry

Cite this

Hamilton, J. A., Steinrauf, L. K., Braden, B. C., Liepnieks, J., Benson, M., Holmgren, G., ... Steen, L. (1993). The X-ray crystal structure refinements of normal human transthyretin and the amyloidogenic Val-30 → Met variant to 1.7-Å resolution. Journal of Biological Chemistry, 268(4), 2416-2424.

The X-ray crystal structure refinements of normal human transthyretin and the amyloidogenic Val-30 → Met variant to 1.7-Å resolution. / Hamilton, Jean A.; Steinrauf, Larry K.; Braden, Bradford C.; Liepnieks, Juris; Benson, Merrill; Holmgren, Gosta; Sandgren, Ola; Steen, Lars.

In: Journal of Biological Chemistry, Vol. 268, No. 4, 05.02.1993, p. 2416-2424.

Research output: Contribution to journalArticle

Hamilton, JA, Steinrauf, LK, Braden, BC, Liepnieks, J, Benson, M, Holmgren, G, Sandgren, O & Steen, L 1993, 'The X-ray crystal structure refinements of normal human transthyretin and the amyloidogenic Val-30 → Met variant to 1.7-Å resolution', Journal of Biological Chemistry, vol. 268, no. 4, pp. 2416-2424.
Hamilton, Jean A. ; Steinrauf, Larry K. ; Braden, Bradford C. ; Liepnieks, Juris ; Benson, Merrill ; Holmgren, Gosta ; Sandgren, Ola ; Steen, Lars. / The X-ray crystal structure refinements of normal human transthyretin and the amyloidogenic Val-30 → Met variant to 1.7-Å resolution. In: Journal of Biological Chemistry. 1993 ; Vol. 268, No. 4. pp. 2416-2424.
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