本文選題：單核苷酸多態(tài)性 + 甲狀腺激素受體��； 參考：《蘭州大學(xué)》2014年碩士論文

【摘要】：甲狀腺激素,通過與核受體超家族蛋白體系中的甲狀腺激素受體α與β受體結(jié)合,并改變其相應(yīng)轉(zhuǎn)錄活性,從而對人體內(nèi)穩(wěn)態(tài)平衡、發(fā)育和新陳代謝等多項(xiàng)生理功能扮演著舉足輕重的作用。甲狀腺激素受體通過與疏水性配體結(jié)合,進(jìn)而影響下游相關(guān)基因表達(dá)。甲狀腺激素受體編碼區(qū)存在多種單核苷酸多態(tài)性突變位點(diǎn),并能引起與人體相關(guān)的各種疾病如甲狀腺激素抵抗綜合癥、癌癥等。這些與疾病相關(guān)的單核苷酸多態(tài)性突變蛋白除其相應(yīng)多樣性以外,還具有一個(gè)共同的特性,即與野生型相比均表現(xiàn)出一種負(fù)性拮抗效應(yīng),從而具有與野生型激素受體不同的生理作用。大量報(bào)道證實(shí),甲狀腺激素受體單核苷酸多態(tài)性與人體內(nèi)多種疾病有關(guān),所以研究單核苷酸多態(tài)性突變型受體與配體的關(guān)系對于研究與甲狀腺激素受體蛋白突變導(dǎo)致的相關(guān)的癌癥具有重要意義。 在本論文中,我們利用分子動力學(xué)模擬方法,在分子水平上對甲狀腺激素受體野生型蛋白及單核苷酸多態(tài)性所誘導(dǎo)的突變蛋白進(jìn)行分析與對比研究。本論文詳細(xì)闡述了影響甲狀腺激素受體整體蛋白突變前后與甲狀腺激素結(jié)合的關(guān)鍵分子機(jī)制和結(jié)構(gòu)特色,甲狀腺激素和甲狀腺激素受體結(jié)合模式、氫鍵網(wǎng)絡(luò)變化、疏水口袋大小變化等。通過在原子水平上對蛋白動力學(xué)特性進(jìn)行分析研究,能幫助我們理解突變后甲狀腺激素受體蛋白中某些特定區(qū)域發(fā)生較大的結(jié)構(gòu)改變,并導(dǎo)致與配體相互作用的重要氨基酸發(fā)生構(gòu)象變化,并最終導(dǎo)致甲狀腺激素與周邊氨基酸的親和力減弱或消失。研究結(jié)果對單核苷酸多態(tài)性突變對甲狀腺激素受體蛋白結(jié)構(gòu)變化,并最終導(dǎo)致甲狀腺激素與其結(jié)合力的影響進(jìn)行了詳盡闡述,并有助于研究SNP有關(guān)的癌癥有關(guān)的致病機(jī)理,以及為后續(xù)的藥物研發(fā)提供一定的信息。
[Abstract]:Thyroid hormone, by binding to the thyroid hormone receptor 偽 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.
【學(xué)位授予單位】：蘭州大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2014
【分類號】：R914

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相關(guān)期刊論文 前1條

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本文編號：1766496