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PDBsum entry 2gab
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Hormone/growth factor
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PDB id
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2gab
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References listed in PDB file
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Key reference
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Title
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Hydroxylated polychlorinated biphenyls selectively bind transthyretin in blood and inhibit amyloidogenesis: rationalizing rodent pcb toxicity.
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Authors
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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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Ref.
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Chem Biol, 2004,
11,
1719-1728.
[DOI no: ]
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PubMed id
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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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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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