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* Residue conservation analysis
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PDB id:
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Hormone/growth factor
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Title:
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Human transthyretin (ttr) complexed with hydroxylated polychlorinated biphenyl-4-hydroxy-3,3',5,4'-tetrachlorobiphenyl
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Structure:
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Transthyretin. Chain: a, b. Synonym: prealbumin, tbpa, ttr, attr. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: ttr, palb. Expressed in: escherichia coli. Expression_system_taxid: 562.
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Biol. unit:
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Tetramer (from PDB file)
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Resolution:
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1.85Å
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R-factor:
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0.211
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R-free:
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0.238
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Authors:
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S.K.Palaninathan,C.Smith,S.H.Safe,J.W.Kelly,J.C.Sacchettini
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Key ref:
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H.E.Purkey
et al.
(2004).
Hydroxylated polychlorinated biphenyls selectively bind transthyretin in blood and inhibit amyloidogenesis: rationalizing rodent PCB toxicity.
Chem Biol,
11,
1719-1728.
PubMed id:
DOI:
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Date:
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08-Mar-06
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Release date:
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21-Mar-06
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PROCHECK
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Headers
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References
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DOI no:
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Chem Biol
11:1719-1728
(2004)
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PubMed id:
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Hydroxylated polychlorinated biphenyls selectively bind transthyretin in blood and inhibit amyloidogenesis: rationalizing rodent PCB toxicity.
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H.E.Purkey,
S.K.Palaninathan,
K.C.Kent,
C.Smith,
S.H.Safe,
J.C.Sacchettini,
J.W.Kelly.
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ABSTRACT
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Polychlorinated biphenyls (PCBs) and their hydroxylated metabolites (OH-PCBs)
are known to bind to transthyretin (TTR) in vitro, possibly explaining their
bioaccumulation, rodent toxicity, and presumed human toxicity. Herein, we show
that several OH-PCBs bind selectively to TTR in blood plasma; however, only one
of the PCBs tested binds TTR in plasma. Some of the OH-PCBs displace thyroid
hormone (T4) from TTR, rationalizing the toxicity observed in rodents, where TTR
is the major T4 transporter. Thyroid binding globulin and albumin are the major
T4 carriers in humans, making it unlikely that enough T4 could be displaced from
TTR to be toxic. OH-PCBs are excellent TTR amyloidogenesis inhibitors in vitro
because they bind to the TTR tetramer, imparting kinetic stability under
amyloidogenic denaturing conditions. Four OH-PCB/TTR cocrystal structures
provide further insight into inhibitor binding interactions.
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Selected figure(s)
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Figure 1.
Figure 1. Compounds Evaluated in This Study
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Figure 3.
Figure 3. OH-PCB Inhibition of TTR Fibril Formation
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The above figures are
reprinted
by permission from Cell Press:
Chem Biol
(2004,
11,
1719-1728)
copyright 2004.
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Figures were
selected
by an automated process.
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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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P.Langer
(2010).
The impacts of organochlorines and other persistent pollutants on thyroid and metabolic health.
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Front Neuroendocrinol,
31,
497-518.
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S.Choi,
N.Reixach,
S.Connelly,
S.M.Johnson,
I.A.Wilson,
and
J.W.Kelly
(2010).
A substructure combination strategy to create potent and selective transthyretin kinetic stabilizers that prevent amyloidogenesis and cytotoxicity.
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J Am Chem Soc,
132,
1359-1370.
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PDB codes:
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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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F.Ucán-Marín,
A.Arukwe,
A.Mortensen,
G.W.Gabrielsen,
G.A.Fox,
and
R.J.Letcher
(2009).
Recombinant Transthyretin Purification and Competitive Binding with Organohalogen Compounds in Two Gull Species (Larus argentatus and Larus hyperboreus).
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Toxicol Sci,
107,
440-450.
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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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S.M.Johnson,
S.Connelly,
I.A.Wilson,
and
J.W.Kelly
(2009).
Toward optimization of the second aryl substructure common to transthyretin amyloidogenesis inhibitors using biochemical and structural studies.
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J Med Chem,
52,
1115-1125.
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PDB codes:
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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,
and
G.Valencia
(2009).
Iodine atoms: a new molecular feature for the design of potent transthyretin fibrillogenesis inhibitors.
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PLoS ONE,
4,
e4124.
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PDB codes:
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S.M.Johnson,
S.Connelly,
I.A.Wilson,
and
J.W.Kelly
(2008).
Toward optimization of the linker substructure common to transthyretin amyloidogenesis inhibitors using biochemical and structural studies.
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J Med Chem,
51,
6348-6358.
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PDB codes:
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J.S.Park,
L.Linderholm,
M.J.Charles,
M.Athanasiadou,
J.Petrik,
A.Kocan,
B.Drobna,
T.Trnovec,
A.Bergman,
and
I.Hertz-Picciotto
(2007).
Polychlorinated biphenyls and their hydroxylated metabolites (OH-PCBS) in pregnant women from eastern Slovakia.
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Environ Health Perspect,
115,
20-27.
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J.Verreault,
S.Shahmiri,
G.W.Gabrielsen,
and
R.J.Letcher
(2007).
Organohalogen and metabolically-derived contaminants and associations with whole body constituents in Norwegian Arctic glaucous gulls.
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Environ Int,
33,
823-830.
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R.T.Zoeller
(2007).
Environmental chemicals impacting the thyroid: targets and consequences.
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Thyroid,
17,
811-817.
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Y.Sekijima,
M.A.Dendle,
and
J.W.Kelly
(2006).
Orally administered diflunisal stabilizes transthyretin against dissociation required for amyloidogenesis.
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Amyloid,
13,
236-249.
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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
