PDBsum entry 1tlm

Transport(thyroxine)

PDB id: 1tlm

Contents

Protein chain

123 a.a. *

Ligands

MIL ×2

Waters ×130

* Residue conservation analysis

References listed in PDB file

Key reference

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

Note In the PDB file this reference is annotated as "TO BE PUBLISHED". The citation details given above were identified by an automated search of PubMed on title and author names, giving a percentage match of 95%.

Abstract

The crystal structure of human transthyretin (TTR) complexed with milrinone (2-methyl-5-cyano-3,4'-bipyridin-6(1H)-one), a positive inotropic cardiac agent, has been refined to R = 17.4% for 8-1.9-A resolution data. This report provides the first detailed description of protein interactions for an inotropic bipyridine agent which is an effective thyroid hormone binding competitor to transthyretin. Milrinone is bound along the 2-fold axis in the binding site with its substituted pyridone ring located deep within the channel of the two identical binding domains of the TTR tetramer. In this orientation the 5-cyano group occupies the same site as the 3'-iodine in the TTR complex with 3,3'-diiodothyronine (Wojtczak, A., Luft, J., and Cody, V. (1992) J. Biol. Chem. 267, 353-357), which is 3.5 A deeper in the channel than thyroxine (Blake, C. C. F., and Oately, S. J., (1977) Nature 268, 115-120). These structural results confirm computer modeling studies of milrinone structural homology with thyroxine and its TTR binding interactions and explain the effectiveness of milrinone competition for thyroxine binding to TTR. To understand the weaker binding affinity of the parent inotropic drug, amrinone (5-amino-3,4'-bipyridin-6(1H)-one), modeling studies of its TTR binding were carried out which indicate that the 5-amino group cannot participate in strong interactions with TTR and the lack of the 2-methyl further weakens amrinone binding.

Secondary reference #1

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 #2

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 #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

Secondary reference #4

Title

Author

R.J.Feldmann.

Ref.

atlas of macromolecular ...

Secondary reference #5

Title

Author

M.O.Dayhoff.

Ref.

atlas of protein sequence, 1976, 5, 265.

Secondary reference #6

Title

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

Ref.

J Mol Biol, 1974, 88, 1. [DOI no: 10.1016/0022-2836(74)90291-5]

PubMed id

4216640

Figure 6.
FIG. 6. A stereo-view of the prealbumin tetramer down the molecular y'axis. N - residue 10; C E reidue 126. T--- T represents the tw di-iodotyrosyl residues of thyroxine located on the molecular c-axis.

Figure 7.
FIG. 7. A stereo-view of the prealbumin tetramer looking down the molecular z-axis, shown by the dot, with the molecular x' and y'-&is horizontal and vertical, respectively, The thyroxine binding sites are superposed along the zaxis.

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

Secondary reference #7

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