PDBsum entry 2rox

Transport

PDB id: 2rox

Contents

Protein chain

118 a.a. *

Ligands

SO4

T44 ×2

Waters ×131

* Residue conservation analysis

References listed in PDB file

Key reference

Title

Structures of human transthyretin complexed with thyroxine at 2.0 a resolution and 3',5'-Dinitro-N-Acetyl-L-Thyronine at 2.2 a resolution.

Authors

A.Wojtczak, V.Cody, J.R.Luft, W.Pangborn.

Ref.

Acta Crystallogr D Biol Crystallogr, 1996, 52, 758-765. [DOI no: 10.1107/S0907444996003046]

PubMed id

15299640

Abstract

The molecular structures of two human transthyretin (hTTR, prealbumin) complexes, co-crystallized with thyroxine (3,5,3',5'-tetraiodo-L-thyronine; T(4)), and with 3',5'-dinitro-N-acetyl-LL-thyronine (DNNAT), were determined by X-ray diffraction methods. Crystals of both structures are orthorhombic, space group P2(1)2(1)2, and have two independent monomers in the asymmetric unit of the crystal lattice. These structures have been refined to 17.0% for 8-2.0 A resolution data for the T(4) complex (I), and to R = 18.4% for 8-2.2 A resolution data for the DNNAT structure (II). This report provides a detailed description of T(4) binding to wild-type hTTR at 2.0 A resolution, as well as DNNAT. In both structures, the two independent hormone-binding sites of the TTR tetramer are occupied by ligand. A 50% statistical disorder model was applied to account for the crystallographic twofold symmetry along the binding channel and the lack of such symmetry for the ligands. Results for the co-crystallized T(4) complex show that T(4) binds deep in the hormone-binding channel and displaces the bound water previously reported for T(4) soaked into a native transthyretin crystal [Blake & Oatley (1977). Nature (London), 268, 115-120]. DNNAT also binds deeper in the channel toward the tetramer center than T(4) with the nitro groups occupying the symmetrical innermost halogen pockets. The N-acetyl moiety does not form polar contacts with the protein side chains as it is oriented toward the center of the channel. The weak binding affinity of DNNAT results from the loss of hydrophobic interactions with the halogen binding pockets as observed in T(4) binding. These data suggest that the halogen-binding sites toward the tetramer center are of primary importance as they are occupied by analogues with weak affinity to TTR, and are therefore selected over the other halogen sites which contribute more strongly to the overall binding affinity.

Figure 1.
Fig. 1. The a-carbon representation of the human transthyretin quaternary structure showing the two independent monomeric subunits A and B forming the twofold-related tetramer with monomers labeled A' and B'. The tetramer is projected down the a axis. The van der Waals surface of thyroxine is shown in the TTR-binding sites.

Figure 3.
Fig. 3. Omit (F o -F,) electron-density map, contoured at 5or, for hTTR-T 4 indicating the iodine positions of thyroxine in binding domain A. This model shows that the hormone binds with its phenolic ring near the tetramer center.

The above figures are reprinted by permission from the IUCr: Acta Crystallogr D Biol Crystallogr (1996, 52, 758-765) copyright 1996.

Secondary reference #1

Title

Structural aspects of inotropic bipyridine binding. Crystal structure determination to 1.9 a of the human serum transthyretin-Milrinone complex.

Authors

A.Wojtczak, J.R.Luft, V.Cody.

Ref.

J Biol Chem, 1993, 268, 6202-6206.

PubMed id

8454595

Secondary reference #2

Title

Mechanism of molecular recognition. Structural aspects of 3,3'-Diiodo-L-Thyronine binding to human serum transthyretin.

Authors

A.Wojtczak, J.Luft, V.Cody.

Ref.

J Biol Chem, 1992, 267, 353-357.

PubMed id

1730601

Secondary reference #3

Title

Crystal structure determination at 2.3-A resolution of human transthyretin-3',5'-Dibromo-2',4,4',6-Tetrahydroxyaurone complex.

Authors

E.Ciszak, V.Cody, J.R.Luft.

Ref.

Proc Natl Acad Sci U S A, 1992, 89, 6644-6648. [DOI no: 10.1073/pnas.89.14.6644]

PubMed id

1631168

Secondary reference #4

Title

Protein-Dna and protein-Hormone interactions in prealbumin: a model of the thyroid hormone nuclear receptor?

Authors

C.C.Blake, S.J.Oatley.

Ref.

Nature, 1977, 268, 115-120.

PubMed id

201845

Secondary reference #5

Title

Structure of human plasma prealbumin at 2.5 a resolution. A preliminary report on the polypeptide chain conformation, Quaternary structure and thyroxine binding

Authors

C.C.F.Blake, M.J.Geisow, I.D.Swan, C.Rerat, B.Rerat.

Ref.

atlas of macromolecular 549 1976 structure on microfiche atlas of protein sequence, 1976, 5, 265.

Secondary reference #6

Title

An X-Ray study of the subunit structure of prealbumin.

Authors

C.C.Blake, I.D.Swan, C.Rerat, J.Berthou, A.Laurent, B.Rerat.

Ref.

J Mol Biol, 1971, 61, 217-224. [DOI no: 10.1016/0022-2836(71)90218-X]

PubMed id

5146194

Figure 1.
FIG. . The ymmetry relations of a) 222, (b) P212,2 and (c) 222 projectd own the c-axis. he origin of 21212 has been hifted from ts onventional position to O,O,) to show its relation- hip o I222 ore learly.

The above figure is reproduced from the cited reference with permission from Elsevier