PDBsum entry 1e3f

Transport(thyroxine)

PDB id: 1e3f

Contents

Protein chain

116 a.a. *

Waters ×78

* Residue conservation analysis

References listed in PDB file

Key reference

Title

Structure of human transthyretin complexed with bromophenols: a new mode of binding.

Authors

M.Ghosh, I.A.Meerts, A.Cook, A.Bergman, A.Brouwer, L.N.Johnson.

Ref.

Acta Crystallogr D Biol Crystallogr, 2000, 56, 1085-1095. [DOI no: 10.1107/S0907444900008568]

PubMed id

10957627

Abstract

The binding of two organohalogen substances, pentabromophenol (PBP) and 2,4,6-tribromophenol (TBP), to human transthyretin (TTR), a thyroid hormone transport protein, has been studied by in vitro competitive binding assays and by X-ray crystallography. Both compounds bind to TTR with high affinity, in competition with the natural ligand thyroxine (T(4)). The crystal structures of the TTR-PBP and TTR-TBP complexes show some unusual binding patterns for the ligands. They bind exclusively in the 'reversed' mode, with their hydroxyl group pointing towards the mouth of the binding channel and in planes approximately perpendicular to that adopted by the T(4) phenolic ring in a TTR-T(4) complex, a feature not observed before. The hydroxyl group in the ligands, which was previously thought to be a key ingredient for a strong binding to TTR, does not seem to play an important role in the binding of these compounds to TTR. In the TTR-PBP complex, it is primarily the halogens which interact with the TTR molecule and therefore must account for the strong affinity of binding. The interactions with the halogens are smaller in number in TTR-TBP and there is a decrease in affinity, even though the interaction with the hydroxyl group is stronger than that in the TTR-PBP complex.

Figure 1.
Figure 1 Schematic diagram of pentabromophenol, 2,4,6-tribromophenol and thyroxine.

Figure 6.
Figure 6 Superposed view of thyroxine on the ligand PBP at the TTR-PBP binding site. (a) In its principal binding mode PBP1, the Br atoms Br2 and Br6 occupy the outer pockets of thyroxine while (b) in the secondary binding mode PBP2, Br3 and Br5 are in the inner pockets of the hormone. I atoms are shown in gold and Br atoms are in rust red. The figures were created using the program XOBJECTS (M. E. M. Noble, unpublished program).

The above figures are reprinted by permission from the IUCr: Acta Crystallogr D Biol Crystallogr (2000, 56, 1085-1095) copyright 2000.

Secondary reference #1

Title

Multiple modes of binding of thyroid hormones and other iodothyronines to human plasma transthyretin

Authors

De la paz, J.M.Burridge, S.J.Oatley, C.C.F.Blake.

Ref.

the design of drugs to ...

Secondary reference #2

Title

Structure of prealbumin: secondary, Tertiary and quaternary interactions determined by fourier refinement at 1.8 a.

Authors

C.C.Blake, M.J.Geisow, S.J.Oatley, B.Rérat, C.Rérat.

Ref.

J Mol Biol, 1978, 121, 339-356. [DOI no: 10.1016/0022-2836(78)90368-6]

PubMed id

671542

Figure 7.
FIG. 7. Stereo drawg of he nternal water structure. Thick and thin lines isinuih the 2 rnonorners n the dimer. a) Shows the hydrogen ond network involving he water molecules, and b) their local nvironment in he imer.

Figure 11.
FIQ. 11. Stereo drawing of the association of he DAGHH''A'U' hot% from ach ime1 looking down the axis with own and acmss. It, s n quivalent view t,o ig. (a) and the right-hand diagram of Fig. 9. The imer-dimw inbfaces arc ocated at, he edges of his truct,nrr.

The above figures are reproduced from the cited reference with permission from Elsevier

Secondary reference #3

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