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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Gaining ligand selectivity in thyroid hormone receptors via entropy
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Gaining ligand selectivity in thyroid hormone receptors via entropy

机译：通过熵获得甲状腺激素受体的配体选择性

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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 β (TRβ) vs. TRa 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 TRβ selectivity. TR x-ray structures reveal better fit of ligand with the TRα LBC. The TRβ LBC, however, expands relative to TRa 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 TRβ and permits greater flexibility of the Triac carboxylate group in TRβ than in TRa. 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.
机译：核受体是药物的重要靶标，但家族成员之间的相似性导致难以获得高度选择性的化合物。对甲状腺激素（TH）受体β（TRβ）和TRa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TRβ-选择性结合很重要。在原子水平上表征了3个选择性配体（GC-1，KB141和GC-24）的结合。优先结合取决于TRβ配体结合腔（LBC）中的非保守残基（Asn-331β），GC-24通过将庞大的侧基插入仅通过该配体打开的LBC延伸而获得额外的选择性。在这里，我们报道天然的TH 3,5,3-三碘甲状腺乙酸（​​Triac）表现出以前无法识别的TRβ选择性机制。 TR X射线结构揭示了配体与TRαLBC的更好配合。然而，在存在三端双向可控硅开关元件的情况下，TRβLBC相对于TRa膨胀（549 A〜3对461 A〜3），并且分子动力学模拟表明水占据了额外的空间。增加的溶剂化作用补偿了配体与TRβ的较弱相互作用，并使TRβ中的Triac羧酸酯基的柔韧性大于TRa。我们提出，这种效应导致较低的熵约束，并降低了双向可控硅和TRβ之间相互作用的自由能，从而解释了亚型选择性结合。在核受体药物设计中可能会利用类似的作用。

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  • 作者

    Leandro Martinez; Alessandro S. Nascimento; Fabio M. Nunes; Kevin Phillips; Ricardo Aparicio; Sandra Martha G. Dias; Ana Carolina M. Figueira; Jean H. Lin; Phuong Nguyen; James W. Apriletti; Francisco A. R. Neves; John D. Baxter; Paul Webb; Munir S. Skaf; Igor Polikarpov;

  • 作者单位

    Instituto de Quimica, Universidade Estadual de Campinas, SP 13084-862, Campinas, Brazil;

    Instituto de Fisica de Sao Carlos, Departamento de Fisica e Informatica, Universidade de Sao Paulo, SP 13566-590, Sao Carlos, Brazil;

    Instituto de Fisica de Sao Carlos, Departamento de Fisica e Informatica, Universidade de Sao Paulo, SP 13566-590, Sao Carlos, Brazil;

    Methodist Hospital Research Institute, Houston, TX 77030;

    Instituto de Fisica de Sao Carlos, Departamento de Fisica e Informatica, Universidade de Sao Paulo, SP 13566-590, Sao Carlos, Brazil Instituto de Quimica, Universidade Estadual de Campinas, Cx. P. 6154, Campinas, SP 13084-862, Brazil;

    Instituto de Fisica de Sao Carlos, Departamento de Fisica e Informatica, Universidade de Sao Paulo, SP 13566-590, Sao Carlos, Brazil C3-137, Molecular Medicine, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853;

    Instituto de Fisica de Sao Carlos, Departamento de Fisica e Informatica, Universidade de Sao Paulo, SP 13566-590, Sao Carlos, Brazil;

    Methodist Hospital Research Institute, Houston, TX 77030;

    Methodist Hospital Research Institute, Houston, TX 77030;

    Methodist Hospital Research Institute, Houston, TX 77030;

    Laboratorio de Farmacologia Molecular, Faculdade de Ciencias de Saude, Universidade de Brasilia, Campus Universitario Darcy Ribeiro, DF 70910-900, Brasilia, Brazil;

    Methodist Hospital Research Institute, Houston, TX 77030;

    Methodist Hospital Research Institute, Houston, TX 77030;

    Instituto de Quimica, Universidade Estadual de Campinas, SP 13084-862, Campinas, Brazil;

    Instituto de Fisica de Sao Carlos, Departamento de Fisica e Informatica, Universidade de Sao Paulo, SP 13566-590, Sao Carlos, Brazil;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    Triac; design; mobility;

    机译：双向可控硅设计;流动性;

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