期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2009
卷号：106
期号：49
页码：20717-20722
DOI：10.1073/pnas.0911024106
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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} (TR{beta}) vs. TR{alpha} reduce cholesterol and fat without effects on heart rate; thus, it is important to understand TR{beta}-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-331{beta}) in the TR{beta} 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 TR{beta} selectivity. TR x-ray structures reveal better fit of ligand with the TR{alpha} LBC. The TR{beta} LBC, however, expands relative to TR{alpha} in the presence of Triac (549 A3 vs. 461 A3), and molecular dynamics simulations reveal that water occupies the extra space. Increased solvation compensates for weaker interactions of ligand with TR{beta} and permits greater flexibility of the Triac carboxylate group in TR{beta} than in TR{alpha}. We propose that this effect results in lower entropic restraint and decreases free energy of interactions between Triac and TR{beta
