Gaining ligand selectivity in thyroid hormone receptors via entropy
Gaining ligand selectivity in thyroid hormone receptors via entropy
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DOI：
10.1073/pnas.0911024106
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发表时间：
2009-12-08
影响因子：
11.1
通讯作者：
Polikarpov, Igor
中科院分区：
文献类型：
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作者：
Martinez, Leandro;Nascimento, Alessandro S.;Polikarpov, Igor
核受体是药物的重要靶点，但家族成员之间的相似性导致难以获得高选择性化合物。对甲状腺激素（TH）受体β（TR β）与TR α具有选择性的合成配体可降低胆固醇和脂肪，而不会影响心率;因此，了解TR β选择性结合非常重要。在原子水平上表征了3种选择性配体（GC-1、KB 141和GC-24）的结合;优先结合取决于TR β配体结合腔（LBC）中的非保守残基（Asn-331 β），GC-24通过将大体积侧基插入仅与该配体打开的LBC延伸中获得额外的选择性。在这里，我们报告说，天然TH 3，5，3 '-triodothyroacetic酸（Triac）表现出一种以前未被认识到的TR β选择性机制。TR X射线结构显示配体与TR α LBC更好的拟合。然而，TR β LBC在三端双向可控硅开关的存在下相对于TR α膨胀（549埃（3）对461埃（3）），分子动力学模拟显示水占据了额外的空间。增加的溶剂化补偿配体与TR β的较弱相互作用，并允许TR β中的三端双向可控硅羧酸酯基团比TR α中的更大的灵活性。我们建议，这种效果的结果在较低的熵约束和降低自由能的双向可控硅和TR β之间的相互作用，解释亚型选择性结合。类似的效应可能会被用于核受体药物的设计。
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 angstrom(3) vs. 461 angstrom(3)), 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, explaining subtype-selective binding. Similar effects could potentially be exploited in nuclear receptor drug design.