3M1O

Human Transthyretin (TTR) complexed with 2-((3,5-dichloro-4-hydroxyphenyl)amino)benzoic acid

Summary for 3M1O

• Entry DOI: 10.2210/pdb3m1o/pdb
• Related: 3IPB 3IPE 3IPG
• Descriptor: Transthyretin, 2-[(3,5-dichloro-4-hydroxyphenyl)amino]benzoic acid (3 entities in total)
• Functional Keywords: amyloid, inhibitor, amyloidosis, disease mutation, gamma-carboxyglutamic acid, glycoprotein, hormone, neuropathy, secreted, thyroid hormone, transport
• Biological source: Homo sapiens (human)
• Cellular location: Secreted: P02766
• Total number of polymer chains: 2
• Total formula weight: 28150.96

Authors

Kolstoe, S.E.,Wood, S.P. (deposition date: 2010-03-05, release date: 2010-11-17, Last modification date: 2023-09-06)

Primary citation

Kolstoe, S.E.,Mangione, P.P.,Bellotti, V.,Taylor, G.W.,Tennent, G.A.,Deroo, S.,Morrison, A.J.,Cobb, A.J.,Coyne, A.,McCammon, M.G.,Warner, T.D.,Mitchell, J.,Gill, R.,Smith, M.D.,Ley, S.V.,Robinson, C.V.,Wood, S.P.,Pepys, M.B.
Trapping of palindromic ligands within native transthyretin prevents amyloid formation.
Proc.Natl.Acad.Sci.USA, 107:20483-20488, 2010

PubMed Abstract: Transthyretin (TTR) amyloidosis is a fatal disease for which new therapeutic approaches are urgently needed. We have designed two palindromic ligands, 2,2'-(4,4'-(heptane-1,7-diylbis(oxy))bis(3,5-dichloro-4,1-phenylene)) bis(azanediyl)dibenzoic acid (mds84) and 2,2'-(4,4'-(undecane-1,11-diylbis(oxy))bis(3,5-dichloro-4,1-phenylene)) bis(azanediyl)dibenzoic acid (4ajm15), that are rapidly bound by native wild-type TTR in whole serum and even more avidly by amyloidogenic TTR variants. One to one stoichiometry, demonstrable in solution and by MS, was confirmed by X-ray crystallographic analysis showing simultaneous occupation of both T4 binding sites in each tetrameric TTR molecule by the pair of ligand head groups. Ligand binding by native TTR was irreversible under physiological conditions, and it stabilized the tetrameric assembly and inhibited amyloidogenic aggregation more potently than other known ligands. These superstabilizers are orally bioavailable and exhibit low inhibitory activity against cyclooxygenase (COX). They offer a promising platform for development of drugs to treat and prevent TTR amyloidosis.

PubMed: 21059958
DOI: 10.1073/pnas.1008255107

Experimental method

X-RAY DIFFRACTION (1.2 Å)