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PDBsum entry 3fc8
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Hormone binding protein
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PDB id
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3fc8
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Contents |
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* Residue conservation analysis
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Plos One
4:e4124
(2009)
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PubMed id:
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Iodine atoms: a new molecular feature for the design of potent transthyretin fibrillogenesis inhibitors.
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T.Mairal,
J.Nieto,
M.Pinto,
M.R.Almeida,
L.Gales,
A.Ballesteros,
J.Barluenga,
J.J.Pérez,
J.T.Vázquez,
N.B.Centeno,
M.J.Saraiva,
A.M.Damas,
A.Planas,
G.Arsequell,
G.Valencia.
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ABSTRACT
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The thyroid hormone and retinol transporter protein known as transthyretin (TTR)
is in the origin of one of the 20 or so known amyloid diseases. TTR self
assembles as a homotetramer leaving a central hydrophobic channel with two
symmetrical binding sites. The aggregation pathway of TTR into amiloid fibrils
is not yet well characterized but in vitro binding of thyroid hormones and other
small organic molecules to TTR binding channel results in tetramer stabilization
which prevents amyloid formation in an extent which is proportional to the
binding constant. Up to now, TTR aggregation inhibitors have been designed
looking at various structural features of this binding channel others than its
ability to host iodine atoms. In the present work, greatly improved inhibitors
have been designed and tested by taking into account that thyroid hormones are
unique in human biochemistry owing to the presence of multiple iodine atoms in
their molecules which are probed to interact with specific halogen binding
domains sitting at the TTR binding channel. The new TTR fibrillogenesis
inhibitors are based on the diflunisal core structure because diflunisal is a
registered salicylate drug with NSAID activity now undergoing clinical trials
for TTR amyloid diseases. Biochemical and biophysical evidence confirms that
iodine atoms can be an important design feature in the search for candidate
drugs for TTR related amyloidosis.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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S.Connelly,
S.Choi,
S.M.Johnson,
J.W.Kelly,
and
I.A.Wilson
(2010).
Structure-based design of kinetic stabilizers that ameliorate the transthyretin amyloidoses.
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Curr Opin Struct Biol,
20,
54-62.
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L.M.Cortez,
R.N.Farías,
and
R.N.Chehín
(2009).
Protective effect of 3,5,3'-triiodothyroacetic and 3,5,3',5'-tetraiodothyroacetic acids on serum albumin fibrillation.
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Eur Biophys J,
38,
857-863.
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P.Sattianayagam,
P.Hawkins,
and
J.Gillmore
(2009).
Amyloid and the GI tract.
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Expert Rev Gastroenterol Hepatol,
3,
615-630.
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S.K.Palaninathan,
N.N.Mohamedmohaideen,
E.Orlandini,
G.Ortore,
S.Nencetti,
A.Lapucci,
A.Rossello,
J.S.Freundlich,
and
J.C.Sacchettini
(2009).
Novel transthyretin amyloid fibril formation inhibitors: synthesis, biological evaluation, and X-ray structural analysis.
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PLoS One,
4,
e6290.
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PDB codes:
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The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
Where a reference describes a PDB structure, the PDB
codes are
shown on the right.
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Links
