甲状腺激素受体样(THR-like)家族是核受体超家族中最大的转录因子家族,它直接与DNA结合并调节基因表达，从而以配体依赖性方式控制各种代谢过程。THR样家族包含受体THR，RARs,VDR,PPAR,RORs,Rev-erbs,汽车,PXR,LXRs,和其他人。THR样受体参与人类健康的许多方面,包括发展,新陈代谢和体内平衡。因此,它被认为是各种疾病如骨质疏松症的重要治疗靶点，病,糖尿病,等。
在这项研究中,我们对跨多个分类单元的类THR家族的配体结合域(LBD)进行了广泛的序列和结构分析.我们使用不同的计算工具（信息理论测量；相对熵）来预测THR样家族的LBD中负责折叠和功能特异性的关键残基。THR样LBD的MSA进一步用作保守研究和系统发育聚类研究的输入。
THR样蛋白的LBD结构域的系统发育分析导致基于其序列同源性的八个亚家族的聚类。通过相对熵（RE）进行的保守性分析表明，结构上重要的残基在整个THR样家族的LBD中是保守的。多和谐保守性分析进一步预测了确定THR样亚家族的LBD中残基的特异性。最后,折叠和功能特异性决定残基(对配体至关重要的残基，DBD和共调节剂结合）定位在甲状腺激素受体蛋白的三维结构上。然后，我们编制了THR样LBD中的天然突变列表，并将它们与折叠和功能特异性突变一起映射。发现一些突变与甲状腺功能减退等严重疾病有关，病,肥胖，脂肪营养不良,癫痫,等。
我们的研究鉴定了THR样LBD中的折叠和功能特异性残基。我们相信这项研究将有助于探索这些残基在不同药物结合中的作用，配体，以及伴侣蛋白之间的蛋白质-蛋白质相互作用。因此，这项研究可能有助于配体或受体的合理设计。
The thyroid hormone receptor-like (THR-like) family is the largest transcription factors family belonging to the nuclear receptor superfamily, which directly binds to DNA and regulates the gene expression and thereby controls various metabolic processes in a ligand-dependent manner. The THR-like family contains receptors THRs, RARs, VDR, PPARs, RORs, Rev-erbs, CAR, PXR, LXRs, and others. THR-like receptors are involved in many aspects of human health, including development, metabolism and homeostasis. Therefore, it is considered an important therapeutic target for various diseases such as osteoporosis, rickets, diabetes, etc.
In this study, we have performed an extensive sequence and structure analysis of the ligand-binding domain (LBD) of the THR-like family spanning multiple taxa. We have use different computational tools (information-theoretic measures; relative entropy) to predict the key residues responsible for fold and functional specificity in the LBD of the THR-like family. The MSA of THR-like LBDs was further used as input in conservation studies and phylogenetic clustering studies.
Phylogenetic analysis of the LBD domain of THR-like proteins resulted in the clustering of eight subfamilies based on their sequence homology. The conservation analysis by relative entropy (RE) revealed that structurally important residues are conserved throughout the LBDs in the THR-like family. The multi-harmony conservation analysis further predicted specificity in determining residues in LBDs of THR-like subfamilies. Finally, fold and functional specificity determining residues (residues critical for ligand, DBD and coregulators binding) were mapped on the three-dimensional structure of thyroid hormone receptor protein. We then compiled a list of natural mutations in THR-like LBDs and mapped them along with fold and function-specific mutations. Some of the mutations were found to have a link with severe diseases like hypothyroidism, rickets, obesity, lipodystrophy, epilepsy, etc.
Our study identifies fold and function-specific residues in THR-like LBDs. We believe that this study will be useful in exploring the role of these residues in the binding of different drugs, ligands, and protein-protein interaction among partner proteins. So this study might be helpful in the rational design of either ligands or receptors.
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