1TLM

STRUCTURAL ASPECTS OF INOTROPIC BIPYRIDINE BINDING: CRYSTAL STRUCTURE DETERMINATION TO 1.9 ANGSTROMS OF THE HUMAN SERUM TRANSTHYRETIN-MILRINONE COMPLEX

Summary for 1TLM

• Entry DOI: 10.2210/pdb1tlm/pdb
• Descriptor: TRANSTHYRETIN, MILRINONE (3 entities in total)
• Functional Keywords: transport(thyroxine)
• Biological source: Homo sapiens (human)
• Cellular location: Secreted: P02766
• Total number of polymer chains: 2
• Total formula weight: 27975.19

Authors

Wojtczak, A.,Luft, J.,Cody, V. (deposition date: 1992-12-22, release date: 1994-01-31, Last modification date: 2024-02-14)

Primary citation

Wojtczak, A.,Luft, J.R.,Cody, V.
Structural aspects of inotropic bipyridine binding. Crystal structure determination to 1.9 A of the human serum transthyretin-milrinone complex.
J.Biol.Chem., 268:6202-6206, 1993

PubMed 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.

PubMed: 8454595

Experimental method

X-RAY DIFFRACTION (1.9 Å)