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研究生:詹瓊如
研究生(外文):Cyong-Ru Jhan
論文名稱:以結構為基礎探討金屬抗生素與神經系統疾病GGGGCC六核苷酸相關結構之結合
論文名稱(外文):Structural basis of the binding of metallo-antibiotic to GGGGCC hexanucleotide related structures seen in neurological diseases
指導教授:侯明宏
口試委員:李以仁張大釗
口試日期:2016-07-28
學位類別:碩士
校院名稱:國立中興大學
系所名稱:生命科學系所
學門:生命科學學門
學類:生物學類
論文種類:學術論文
論文出版年:2016
畢業學年度:104
語文別:中文
論文頁數:123
中文關鍵詞:核酸結構雙股螺旋結構四股螺旋神經系統疾病X光繞射
外文關鍵詞:DNA structuresduplex structureG-quadruplexneurological diseaseX-ray diffraction
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肌萎縮性側索硬化症 (ALS) 是一個成人發病且涉及神經元的死亡的神經退化性疾病,近年研究發現在C9orf72基因的第一個內含子上的GGGGCC六核苷酸重複序列過度擴增,是造成ALS和額顳葉癡呆(FTD) 最常見的原因,過度擴增的GGGGCC DNA序列能夠折疊成穩定的G-四股螺旋和髮夾型結構,並啟動ALS / FTD一系列的致病機制。Chromomycin A3 (Chro) 是一種金屬抗生素(Metallantibiotic) ,Ni(II)會與兩個Chro分子螯合形成二聚體,其作用方式是藉由與DNA小凹槽上的富含GC的序列結合,從而中斷基因的複製和轉錄。ALS與d(GGGGCC)n六核苷酸序列過度擴增密切相關,其中過度擴增的DNA包含許多連續的GGCC結合位。
本篇研究主要針對Ni(II)(Chro)2與GGGGCC之DNA序列結合的生物物理特徵,DNA之熱熔點溫度實驗、圓二色光譜儀以及SPR實驗分析結果指出,不同種類金屬之Metal(II)(Chro)2中,以Ni(II)(Chro)2提升含有GGGGCC 模體(motif) 的序列之穩定性效果最佳,CD實驗結果指出Ni(II)(Chro)2會結合含有GGGGCC 模體的序列,並導致光譜特徵劇烈改變。我們更進一步解析出d(TTGGGCCGAA)和d(TTCGGCCCAA)所形成的雙股螺旋與Ni(II)(Chro)2複合體,Ni(II)(Chro)2會專一性結合到DNA雙股螺旋GGCC結合位後導致DNA小凹槽(minor groove) 變寬,Chro沿著發色團的兩側連接出去的糖基(A/ B環和C / D / E環)會穿過小凹槽包裹DNA磷酸主鏈,且DNA在兩個複合體中都發現約22度與20度的彎曲,DNA- Ni(II)(Chro)2複合體之間有六個專一性的氫鍵,提供Ni(II)(Chro)2對於GGGCCG序列專一性。我們也為了探討d(GGGGCC)4形成的G-四股螺旋與Ni(II)(Chro)2之間的作用,進行DNA之熱熔點溫度實驗、圓二色光譜儀以及SPR實驗分析,SPR實驗結果進行Binding with drifting baseline分析後,發現Ni(II)(Chro)2二聚體會與d(GGGGCC)4所形成之G-四股螺旋結合。本篇實驗結果顯示Ni(II)(Chro)2在生物中可能與GGGGCC六核苷酸重複序列作用的結果。

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease that leads in the death of neuron. Recently, an expanded GGGGCC hexanucleotide repeats in the first intron of C9orf72 was found to be the most common cause of ALS and Frontotemporal dementia (FTD). The expanded GGGGCC DNA sequence is able to fold into stable G-quadruplex and hairpin structures which initiate ALS/FTD pathologies. One metallantibiotic, the Ni(II) complex of dimeric Chromomycin (Chro), has been docummented to function by groove binding to DNA at GC rich sites, thereby interrupting essential biological processes including replication and transcription. ALS are correlated with the expansion of d(GGGGCC)n hexanucleotide sequences, that provide many contiguous GGCC sites for Chro binding.
This study focused on the biophysical characterization of the binding of the Ni(II) complex of dimeric Chro to DNA duplex with GGGGCC motif. Heat denaturation, circular dichroism and surface plasmon resonance analyses showed that duplex DNA with GGGGCC motif sequences are preferred Ni(II)(Chro)2-binding sites. Furthermore, we solved the crystal structure of Ni(II)(Chro)2 bound to d(TTGGGCCGAA/TTCGGCCCAA). The Chro dimer binds at and significantly widens the minor groove of the GGGCCG sequence. The long axis of each chromophore lies along and stacks over the sugar-phosphate backbone with the two attached saccharide moieties (rings A/B and C/D/E) wrapping across the minor groove. DNA is kinked by 22 degrees and 20 degrees in the two complexes, respectively. Six G-specific hydrogen bonds between Chro and DNA provide the GGGCCG sequence specificity. The binding of Ni(II)(Chro)2 to G-quadruplex structure of (GGGGCC)4 were further characterized by heat denaturation, circular dichroism and surface plasmon resonance analyses. The results showed that Ni(II)(Chro)2 is able to interact with the G-quadruplex structure of (GGGGCC)4 via 1:1 binding model. Our results provide evidence of a possible biological consequence of Ni(II)(Chro)2 binding to GGGGCC hexanucleotide repeat sequences.

摘要 i
Abstract ii
目錄 iii
表目次 v
圖目次 vi
第一章、 前言 1
一、 核苷酸重複相關疾病 (nucleotide repeat disease) 1
二、 家族性遺傳ALS/FTD與C9orf72的關係 2
三、 C9orf72導致的致病機制 3
四、 四股螺旋 (quadruplex) 4
五、 DNA 結合藥物 5
(一)、 DNA 結合藥物結合方式分類 5
(二)、 色黴素A3 (Chromomycin A3, Chro ) 6
六、 研究動機 7
第二章、 材料與方法 8
一、 實驗流程 8
二、 實驗方法 9
(一)、 DNA與Chro 定量分析 9
(二)、 DNA之熱熔點溫度 (Melting temperature, Tm) 分析 10
(三)、 圓二色光譜 (ciucular dichroism spectra) 分析 12
(四)、 DNA-Ni(II)(Chro)2 複合物晶體培養 15
(五)、 X光晶體繞射數據收集 17
(六)、 相位角 (Phase) 判定 18
(七)、 晶體繞射數據之結構精修 (Structure Refinement) 及分析 19
(八)、 表面電漿共振 (surface plasmon resonance, SPR) 實驗 19
第三章、 結果 23
一、 Metal(II)(Chro)2對ALS相關DNA序列之熱熔點溫度及穩定性分析 23
二、 以CD分析Ni(II)(Chro)2對ALS相關DNA序列之構型影響 25
三、 DNA- Ni(II)(Chro)2複合體之晶體結構分析 25
(一)、 晶體繞射數據收集 25
(二)、 結構模型建立以及精修結果 26
(三)、 整體結構描述 26
(四)、 雙股DNA主鏈上的扭轉角度參數 28
(五)、 DNA- Ni(II)(Chro)2複合體之結晶排列與堆疊 29
四、 以SPR分析Ni(II)(Chro)2對ALS相關DNA序列之親和性影響 30
五、 Ni(II)(Chro)2對d(GGGGCC)4之熱熔點溫度及穩定性分析 30
六、 以CD分析Ni(II)(Chro)2對d(GGGGCC)4之構型影響 31
七、 以SPR分析Ni(II)(Chro)2對d(GGGGCC)4之親和性影響 32
第四章、 討論 33
一、 小分子藥物與核苷酸重複相關疾病之現況 33
二、 探討ALS相關序列與Ni(II)(Chro)2結合後結構變化 34
三、 Ni(II)(Chro)2二聚體與DNA結合機制研究 35
四、 Hoogsteen base pair之三股螺旋(triplets) 36
五、 Complex I與II和DNA-Metal(II)(Chro)2複合體之結構比較 37
(一)、 和TTGGCCAA-Mg(II)(Chro)2複合體之結構比較 37
(二)、 和TT(CCG)3AA-Ni(II)(Chro)2複合體之結構比較 38
六、 探討小分子藥物對於G-四股螺旋之影響 39
第五章、 結論 41
第六章、 表次 42
第七章、 圖次 56
第八章、 附錄 97
第九章、 補充資料 102
第十章、 參考文獻 112


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