5BOJ

Crystal Structure of Human Transthyretin in Complex with Gemfibrozil

Summary for 5BOJ

• Entry DOI: 10.2210/pdb5boj/pdb
• Related: 4qxv
• Descriptor: Transthyretin, 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid, SODIUM ION, ... (4 entities in total)
• Functional Keywords: transport protein, thyroxine binding, gemfibrozil complex
• Biological source: Homo sapiens (Human)
• Cellular location: Secreted: P02766
• Total number of polymer chains: 2
• Total formula weight: 28078.38

Authors

Begum, A.,Olofsson, A.,Sauer-Eriksson, A.E. (deposition date: 2015-05-27, release date: 2015-08-05, Last modification date: 2024-01-10)

Primary citation

Iakovleva, I.,Brannstrom, K.,Nilsson, L.,Gharibyan, A.L.,Begum, A.,Anan, I.,Walfridsson, M.,Sauer-Eriksson, A.E.,Olofsson, A.
Enthalpic Forces Correlate with the Selectivity of Transthyretin-Stabilizing Ligands in Human Plasma.
J.Med.Chem., 58:6507-6515, 2015

PubMed Abstract: The plasma protein transthyretin (TTR) is linked to human amyloidosis. Dissociation of its native tetrameric assembly is a rate-limiting step in the conversion from a native structure into a pathological amyloidogenic fold. Binding of small molecule ligands within the thyroxine binding site of TTR can stabilize the tetrameric integrity and is a potential therapeutic approach. However, through the characterization of nine different tetramer-stabilizing ligands we found that unspecific binding to plasma components might significantly compromise ligand efficacy. Surprisingly the binding strength between a particular ligand and TTR does not correlate well with its selectivity in plasma. However, through analysis of the thermodynamic signature using isothermal titration calorimetry we discovered a better correlation between selectivity and the enthalpic component of the interaction. This is of specific interest in the quest for more efficient TTR stabilizers, but a high selectivity is an almost universally desired feature within drug design and the finding might have wide-ranging implications for drug design.

PubMed: 26214366
DOI: 10.1021/acs.jmedchem.5b00544

Experimental method

X-RAY DIFFRACTION (1.75 Å)