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PDBsum entry 3jzc
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Transcription
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PDB id
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3jzc
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References listed in PDB file
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Key reference
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Title
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Gaining ligand selectivity in thyroid hormone receptors via entropy.
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Authors
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L.Martínez,
A.S.Nascimento,
F.M.Nunes,
K.Phillips,
R.Aparicio,
S.M.Dias,
A.C.Figueira,
J.H.Lin,
P.Nguyen,
J.W.Apriletti,
F.A.Neves,
J.D.Baxter,
P.Webb,
M.S.Skaf,
I.Polikarpov.
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Ref.
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Proc Natl Acad Sci U S A, 2009,
106,
20717-20722.
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PubMed id
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Abstract
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Nuclear receptors are important targets for pharmaceuticals, but similarities
between family members cause difficulties in obtaining highly selective
compounds. Synthetic ligands that are selective for thyroid hormone (TH)
receptor beta (TRbeta) vs. TRalpha reduce cholesterol and fat without effects on
heart rate; thus, it is important to understand TRbeta-selective binding.
Binding of 3 selective ligands (GC-1, KB141, and GC-24) is characterized at the
atomic level; preferential binding depends on a nonconserved residue
(Asn-331beta) in the TRbeta ligand-binding cavity (LBC), and GC-24 gains extra
selectivity from insertion of a bulky side group into an extension of the LBC
that only opens up with this ligand. Here we report that the natural TH
3,5,3'-triodothyroacetic acid (Triac) exhibits a previously unrecognized
mechanism of TRbeta selectivity. TR x-ray structures reveal better fit of ligand
with the TRalpha LBC. The TRbeta LBC, however, expands relative to TRalpha in
the presence of Triac (549 A(3) vs. 461 A(3)), and molecular dynamics
simulations reveal that water occupies the extra space. Increased solvation
compensates for weaker interactions of ligand with TRbeta and permits greater
flexibility of the Triac carboxylate group in TRbeta than in TRalpha. We propose
that this effect results in lower entropic restraint and decreases free energy
of interactions between Triac and TRbeta, explaining subtype-selective binding.
Similar effects could potentially be exploited in nuclear receptor drug design.
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