Structural determinants of allosteric ligand activation in RXR heterodimers
Structural determinants of allosteric ligand activation in RXR heterodimers
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DOI：
10.1016/s0092-8674(04)00119-9
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发表时间：
2004-02-06
期刊：
影响因子：
64.5
通讯作者：
Ranganathan, R
中科院分区：
文献类型：
--
作者：
Shulman, AI;Larson, C;Ranganathan, R
变构通讯是核受体介导的配体依赖性转录反应的基础。虽然研究已经阐明了参与这一过程的许多组分，但介导变构的受体蛋白内的能量结构仍然未知。使用基于序列的方法，旨在检测蛋白质中的氨基酸的共同进化，称为统计耦合分析（SCA），我们确定了一个网络的能量耦合的残基连接的核受体配体结合域的功能表面。这些预测的残基的功能分析表明，它们参与了一个变构网络，该网络控制异二聚体受体激活转录的能力，以响应配体结合的任何合作伙伴。有趣的是，单个网络残基的突变可以区分内分泌饮食和合成激动剂对受体的激活。这些结果揭示了RXR异二聚体变构通讯所需的结构网络，并表明配体反应的特异性和过氧化物酶共同进化，使信号歧视。
Allosteric communication underlies ligand-dependent transcriptional responses mediated by nuclear receptors. While studies have elucidated many of the components involved in this process, the energetic architecture within the receptor protein that mediates allostery remains unknown. Using a sequence-based method designed to detect coevolution of amino acids in a protein, termed the statistical coupling analysis (SCA), we identify a network of energetically coupled residues that link the functional surfaces of nuclear receptor ligand binding domains. Functional analysis of these predicted residues demonstrates their participation in an allosteric network that governs the ability of heterodimeric receptors to activate transcription in response to ligand binding by either partner. Interestingly, mutation of a single network residue can discriminate between receptor activation by endocrine dietary, and synthetic agonists. These results reveal a structural network required for RXR heterodimer allosteric communication and suggest that the specificity of ligand response and permissivity coevolved to enable signal discrimination.