X-ray crystal structure of the Ala-109 → Thr variant of human transthyretin which produces euthyroid hyperthyroxinemia

Larry K. Steinrauf, Jean A. Hamilton, Bradford C. Braden, Jill R. Murrell, Merrill Benson

Research output: Contribution to journalArticle

62 Citations (Scopus)

Abstract

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 Å. 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 Å for bond distances, 0.5° for bond angles, 0.031 Å for 1-4 distances, and 0.005 Å 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 β 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.

Original languageEnglish
Pages (from-to)2425-2430
Number of pages6
JournalJournal of Biological Chemistry
Volume268
Issue number4
StatePublished - Feb 5 1993

Fingerprint

Hyperthyroxinemia
Prealbumin
Crystal structure
Thyroxine
X-Rays
X rays
Least-Squares Analysis
Proteins
Monomers
Molecular Conformation
Threonine
Conformations
Substitution reactions
Diffraction
Binding Sites
Atoms
Mutation
Molecules
Geometry
Water

ASJC Scopus subject areas

  • Biochemistry

Cite this

X-ray crystal structure of the Ala-109 → Thr variant of human transthyretin which produces euthyroid hyperthyroxinemia. / Steinrauf, Larry K.; Hamilton, Jean A.; Braden, Bradford C.; Murrell, Jill R.; Benson, Merrill.

In: Journal of Biological Chemistry, Vol. 268, No. 4, 05.02.1993, p. 2425-2430.

Research output: Contribution to journalArticle

Steinrauf, Larry K. ; Hamilton, Jean A. ; Braden, Bradford C. ; Murrell, Jill R. ; Benson, Merrill. / X-ray crystal structure of the Ala-109 → Thr variant of human transthyretin which produces euthyroid hyperthyroxinemia. In: Journal of Biological Chemistry. 1993 ; Vol. 268, No. 4. pp. 2425-2430.
@article{549a27480e40437d96043c310a9d0a17,
title = "X-ray crystal structure of the Ala-109 → Thr variant of human transthyretin which produces euthyroid hyperthyroxinemia",
abstract = "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 {\AA}. 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 {\AA} for bond distances, 0.5° for bond angles, 0.031 {\AA} for 1-4 distances, and 0.005 {\AA} 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 β 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.",
author = "Steinrauf, {Larry K.} and Hamilton, {Jean A.} and Braden, {Bradford C.} and Murrell, {Jill R.} and Merrill Benson",
year = "1993",
month = "2",
day = "5",
language = "English",
volume = "268",
pages = "2425--2430",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "4",

}

TY - JOUR

T1 - X-ray crystal structure of the Ala-109 → Thr variant of human transthyretin which produces euthyroid hyperthyroxinemia

AU - Steinrauf, Larry K.

AU - Hamilton, Jean A.

AU - Braden, Bradford C.

AU - Murrell, Jill R.

AU - Benson, Merrill

PY - 1993/2/5

Y1 - 1993/2/5

N2 - 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 Å. 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 Å for bond distances, 0.5° for bond angles, 0.031 Å for 1-4 distances, and 0.005 Å 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 β 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.

AB - 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 Å. 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 Å for bond distances, 0.5° for bond angles, 0.031 Å for 1-4 distances, and 0.005 Å 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 β 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.

UR - http://www.scopus.com/inward/record.url?scp=0027459456&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0027459456&partnerID=8YFLogxK

M3 - Article

C2 - 8428916

AN - SCOPUS:0027459456

VL - 268

SP - 2425

EP - 2430

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 4

ER -