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dc.contributor.authorHsiang-Ti Huangen_US
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dc.description.abstract脫氧肌苷(deoxyinosine, dI)是一種自然發生的鹼基,可以與四種典型鹼基形成鹼基配對,具有不同穩定性,因此在 DNA 複製過程中可能引起突變。另外,dI 可能導致 DNA結合蛋白的識別位點改變,已有研究顯示,肌苷存在於 RNA 編輯中會導致各種疾病的發生,包括癌症,然而,關於肌苷作用於 DNA 鹼基配對的信息很少。棘黴素 (echinomycin) 是 DNA 結合藥物會嵌入於 DNA 鹼基中,干擾 DNA 複製和轉錄。本篇研究是想要了解 echinomycin 與 I:C 錯配結合會對 DNA 結構和穩定性的造成甚麼影響。首先我們想要了解 echinomycin 如何去辨識I:C錯配,所以我們設計出d(ACGICGT)/d(ACGCCGT)含有一個 I:C 錯配的雙股 DNA 序列,並解析出 echinomycin 與 I:C 錯配的晶體結構,結構結果說明,結構中的 I:C 錯配的配對方式為搖擺鹼基對 (Wobble base pair),echinomycin 插入到 DNA 中會造成結構的鹼基間距縮小,但 I:C 錯配會與鄰近的兩個喹喔啉環產生作用,提供整體複合物結構的穩定性,接著使用熱熔點溫度實驗(Tm)來測定,比較在有無藥物的存在下,DNA 之間的 Tm 值(ΔTm)的差異來測量DNA的穩定性。總體來說,echinomycin對I:C錯配會表現出特異的親和力,因此可用於製藥和DNA的試劑開發中。zh_TW
dc.description.abstractDeoxyinosine (dI) is a naturally occurring base which can form base-pairing with all four canonical bases with different stabilities and thus may cause mutations during DNA replication process. Also, the dI may lead to altered recognition sites for DNA binding proteins. It has been shown that the presence of inosine leads to various diseases including cancers during RNA editing, however, very few information is known about the inosine acting in DNA base pairing. Furthermore, the echinomycin is a DNA binding intercalator which inserts into the DNA base pair to interfere transcription and replication. In the current study, we analyzed the effects of echinomycin binding on the structure and stability to I:C mismatched DNA. We solved the crystal structure of echinomycin binding to d(ACGICGT)/ d(ACGCCGT) duplex containing single I:C mismatch to understand the structural details of I:C mismatch recognition by echinomycin. The structural results shows that, insertion of echinomycin into DNA causes structural compression and the I:C base pair flanking bis-intercalator site shows wobble base pairing. Furthermore, the staggered quinoxaline rings of the two echinomycin that surround the I:C mismatch shows the stacking interactions within the duplex which provides the stability to overall complex .The stability of DNA is measured by using melting temperature (Tm) assay to compare differences of Tm (ΔTm) between DNAs in presence and absence of drug.Overall, the echinomycin shows specific affinity to I:C mismatch and thus can have potential applications in pharmaceuticals and DNA based nanotechnology development.en_US
dc.description.tableofcontents目錄 第一章、前言 1 一、鹼基配對 1 二、鹼基的錯配 2 三、脫氧肌苷 3 四、修復機制 4 五、DNA 結合藥物 8 (一)、凹槽結合 (Groove binder) 8 (二)、烷化 (Alkylator) 8 (三)、DNA 斷裂 (DNA cleavage) 8 (四)、嵌入 (Intercalator) 9 六、研究動機 10 第二章、材料與方法 11 一、實驗流程 11 二、實驗方法 12 (一)、 DNA 序列與 echinomycin 定量分析實驗 12 (二)、 DNA 序列與 echinomycin 複合物晶體培養實驗(Crystallization) 13 (三)、 晶體繞射數據收集 17 (四)、 相位角 (Phase) 18 (五)、 晶體結構精修 (Crystal Structure Refinement) 19 (六)、 DNA 序列與 echinomycin 熱熔點溫度分析實驗(Melting temperature,Tm) 20 第三章、結果 23 一、DNA 晶體結構解析之結果 23 (一)、 DNA_Alone整體結構描述 23 (二)、 DNA_Alone結構參數分析 24 (三)、 DNA_Alone結構扭轉角度 24 (四)、 DNA-Echi 複合物整體結構描述 25 (五)、 DNA-Echi 複合物結構參數分析 26 (六)、 DNA-Echi 複合物結構扭轉角度 27 二、DNA 序列與 echinomycin 熱熔點溫度分析實驗之結果 28 第四章、討論 29 一、IC_Alone 結構與其他結構相比 29 二、IC_Alone 與 GC_Alone相比 29 三、GC_Alone 和 GC-Echi 相比 30 四、IC_Alone 和 IC-Echi 相比 30 五、IC-Echi 與其他結構相比 31 六、IC-Echi 與 GC-Echi 結構相比 31 第五章、結論 32 第六章、表次 33 第七章、圖次 45 第八章、補充資料 92 第九章、參考文獻 100 第十章、網路資源 104zh_TW
dc.subjectI:C 錯配鹼基zh_TW
dc.subjectI:C mismatchen_US
dc.titleStructural basis for the binding of echinomycin to DNA duplex containing I:C mismatchen_US
dc.typethesis and dissertationen_US
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