TY - JOUR
T1 - Gaining ligand selectivity in thyroid hormone receptors via entropy
AU - Martínez, Leandro
AU - Nascimento, Alessandro S.
AU - Nunes, Fabio M.
AU - Phillips, Kevin
AU - Aparicio, Ricardo
AU - Dias, Sandra Martha G.
AU - Figueira, Ana Carolina M.
AU - Lin, Jean H.
AU - Nguyen, Phuong
AU - Apriletti, James W.
AU - Neves, Francisco A.R.
AU - Baxter, John D.
AU - Webb, Paul
AU - Skaf, Munir S.
AU - Polikarpov, Igor
PY - 2009/12/8
Y1 - 2009/12/8
N2 - 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 β (TRβ) vs. TRα reduce cholesterol and fat without effects on heart rate; thus, it is important to understand TRβ-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-331β) in the TRβ 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 TRα selectivity. TR x-ray structures reveal better fit of ligand with the TRα LBC. The TRβ LBC, however, expands relative to TRα in the presence of Triac (549 Å3 vs. 461 Å3), and molecular dynamics simulations reveal that water occupies the extra space. Increased solvation compensates for weaker interactions of ligand with TRβ and permits greater flexibility of the Triac carboxylate group in TRβ than in TRα. We propose that this effect results in lower entropic restraint and decreases free energy of interactions between Triac and TRβ, explaining subtype-selective binding. Similar effects could potentially be exploited in nuclear receptor drug design.
AB - 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 β (TRβ) vs. TRα reduce cholesterol and fat without effects on heart rate; thus, it is important to understand TRβ-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-331β) in the TRβ 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 TRα selectivity. TR x-ray structures reveal better fit of ligand with the TRα LBC. The TRβ LBC, however, expands relative to TRα in the presence of Triac (549 Å3 vs. 461 Å3), and molecular dynamics simulations reveal that water occupies the extra space. Increased solvation compensates for weaker interactions of ligand with TRβ and permits greater flexibility of the Triac carboxylate group in TRβ than in TRα. We propose that this effect results in lower entropic restraint and decreases free energy of interactions between Triac and TRβ, explaining subtype-selective binding. Similar effects could potentially be exploited in nuclear receptor drug design.
KW - Design
KW - Mobility
KW - Triac
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U2 - 10.1073/pnas.0911024106
DO - 10.1073/pnas.0911024106
M3 - Article
C2 - 19926848
AN - SCOPUS:73949144655
SN - 0027-8424
VL - 106
SP - 20717
EP - 20722
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 49
ER -