甲状腺激素受体蛋白单核苷酸多态性分子动力学研究

发布时间：2018-04-18 03:05

本文选题：单核苷酸多态性 + 甲状腺激素受体　；参考：《兰州大学》2014年硕士论文

【摘要】：甲状腺激素,通过与核受体超家族蛋白体系中的甲状腺激素受体α与β受体结合,并改变其相应转录活性,从而对人体内稳态平衡、发育和新陈代谢等多项生理功能扮演着举足轻重的作用。甲状腺激素受体通过与疏水性配体结合,进而影响下游相关基因表达。甲状腺激素受体编码区存在多种单核苷酸多态性突变位点,并能引起与人体相关的各种疾病如甲状腺激素抵抗综合症、癌症等。这些与疾病相关的单核苷酸多态性突变蛋白除其相应多样性以外,还具有一个共同的特性,即与野生型相比均表现出一种负性拮抗效应,从而具有与野生型激素受体不同的生理作用。大量报道证实,甲状腺激素受体单核苷酸多态性与人体内多种疾病有关,所以研究单核苷酸多态性突变型受体与配体的关系对于研究与甲状腺激素受体蛋白突变导致的相关的癌症具有重要意义。在本论文中,我们利用分子动力学模拟方法,在分子水平上对甲状腺激素受体野生型蛋白及单核苷酸多态性所诱导的突变蛋白进行分析与对比研究。本论文详细阐述了影响甲状腺激素受体整体蛋白突变前后与甲状腺激素结合的关键分子机制和结构特色,甲状腺激素和甲状腺激素受体结合模式、氢键网络变化、疏水口袋大小变化等。通过在原子水平上对蛋白动力学特性进行分析研究,能帮助我们理解突变后甲状腺激素受体蛋白中某些特定区域发生较大的结构改变,并导致与配体相互作用的重要氨基酸发生构象变化,并最终导致甲状腺激素与周边氨基酸的亲和力减弱或消失。研究结果对单核苷酸多态性突变对甲状腺激素受体蛋白结构变化,并最终导致甲状腺激素与其结合力的影响进行了详尽阐述,并有助于研究SNP有关的癌症有关的致病机理,以及为后续的药物研发提供一定的信息。
[Abstract]:Thyroid hormone, by binding to the thyroid hormone receptor 伪 and 尾 receptor in the nuclear receptor superfamily protein system, and changing its corresponding transcriptional activity, thus balances the homeostasis of human body.Many physiological functions, such as development and metabolism, play an important role.Thyroid hormone receptors affect downstream gene expression by binding to hydrophobic ligands.There are many single nucleotide polymorphisms in the coding region of thyroid hormone receptor which can cause various diseases related to human body such as thyroid hormone resistance syndrome cancer and so on.In addition to their corresponding diversity, these disease-related SNP proteins share a common characteristic, that is, they all exhibit a negative antagonistic effect compared with wild type.Therefore, it has different physiological effects from wild type hormone receptors.A large number of reports have confirmed that thyroid hormone receptor single nucleotide polymorphisms are associated with many diseases in the human body.Therefore, it is important to study the relationship between single nucleotide polymorphism mutant receptor and ligand for the study of cancer associated with thyroid hormone receptor protein mutation.In this paper, we use molecular dynamics simulation method to analyze and compare the mutant proteins induced by thyroid hormone receptor wild type protein and single nucleotide polymorphism at the molecular level.In this paper, the key molecular mechanism and structural characteristics of thyroid hormone binding before and after the whole protein mutation of thyroid hormone receptor, the binding mode of thyroid hormone and thyroid hormone receptor, the changes of hydrogen bond network, were discussed in detail.Changes in the size of the hydrophobic pocket, etc.By analyzing the kinetic characteristics of the protein at the atomic level, we can understand the structural changes in some specific regions of the thyroid hormone receptor protein after mutation.It also leads to the conformation change of important amino acids interacting with ligands, and eventually leads to the weakening or disappearance of the affinity of thyroid hormones to peripheral amino acids.The results of this study illustrate in detail the effects of single nucleotide polymorphism mutations on the structure of thyroid hormone receptor proteins, which ultimately lead to the binding of thyroid hormones to thyroid hormones, and contribute to the study of the carcin-related pathogenesis of SNP.And for the follow-up drug development to provide certain information.
【学位授予单位】：兰州大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R914

【参考文献】