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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 詹迺立(Nei-Li Chan) | |
dc.contributor.author | Ying-Ren Wang | en |
dc.contributor.author | 王英任 | zh_TW |
dc.date.accessioned | 2021-05-19T17:49:00Z | - |
dc.date.available | 2023-03-29 | |
dc.date.available | 2021-05-19T17:49:00Z | - |
dc.date.copyright | 2018-03-29 | |
dc.date.issued | 2017 | |
dc.date.submitted | 2017-09-11 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/7649 | - |
dc.description.abstract | 人類第二型拓樸異構酶 α 亞型 (Top2α) 和 β 亞型 (Top2β) 為目前常用於化學療法治療癌症的細胞標的蛋白。藉由影響酵素本身的催化反應,此類化療藥物增加第二型拓樸異構酶調控的 DNA 斷裂,並且造成 DNA 損傷以進而使細胞死亡,這些化療藥物有效的使第二型拓樸異構酶和 DNA 形成穩定的切割複合體。為了促進開發專一性藥物,我們成功解析了人類 Top2α 亞型酵素與 DNA 及抗癌藥物所形成的切割複合體晶體結構,在酵素與 DNA 的切割複合體中,清楚的看見藥物嵌入由酵素造成的 DNA 斷裂處。基於清楚的 Top2α 亞型結構資訊及實驗室先前對於 Top2β 亞型結構的研究探討,處於活性中心的胺基酸,甲硫氨酸 (Methionine 762) 在 Top2α 亞型及麩醯胺酸 (Glutamine 788) 在 Top2β 亞型具有氨基酸的差異性,可以做為設計藥物的參考。其中在Top2α 亞型活性中心的甲硫氨酸可以用來設計與鉑 (Platinum) 衍生物產生鍵結,增加藥物嵌入 DNA 斷裂處的穩定度,進而生成更為穩定的酵素切割複合體。為了得到專一性藥物,我們設計並且獲得有機鉑化合物 (organoplatinum compound),藉由 cis-dichlorodiammineplatinum(II) 取代 etoposide 的糖官能基並且命名為 etoplatin-N2α、etoplatin-N2β。在 DNA 解超螺旋活性測試中,比起使用 etoposide 作為抑制物,對於 Top2α 亞型及 Top2β 亞型的解超螺旋活性 etoplatin-N2β 具有更好的抑制效果。在 Top2 調控的 DNA 斷裂實驗中,使用 etoposide 為抑制物,仍然有機會使 DNA 重新連接,而使用 etoplatin-N2β 為抑制物時,斷裂的 DNA 無法被有效的重新連接形成不可逆反應。藉由 Top2s亞型酵素與 DNA 及 etoplatin-N2β 所形成的切割複合體晶體結構分析,etoplatin-N2β 的 Pt2+會與甲硫氨酸的 Sδ 產生穩定的配位鍵 (coordinate bond)。然而當完整的藥物結合區域結構被破壞時,這個高度穩定 Pt2+-Sδ 的配位鍵也會隨即斷裂,此一現象證明Pt2+ 與酵素形成的配位鍵可以用來當成結構依賴型的藥物設計,使酵素抑制藥物具有可回復性。我們的實驗結果說明利用甲硫氨酸來針對 Top2α 亞型當成設計專一性藥物是可行的,並且可以減少藥物偏離目標結合至 Top2β 亞型造成的副作用。 | zh_TW |
dc.description.abstract | Human type II topoisomerase (Top2) isoforms, hTop2α and hTop2β, are the cellular targets of some most successful drugs used in anticancer chemotherapy. By interfering with the enzyme’s catalytic cycle, these drugs promote Top2-mediated DNA cleavage to trigger DNA damage-induced cell death pathways. The potency of these drugs relies on effective stabilization of the enzyme-mediated DNA breaks. To facilitate drug development, our lab had performed structural studies on hTopβ and revealed the actions of Top2-targeting anticancer drugs. In this work, we have further determined the structures of hTop2α cleavage core (hTop2αcore) in complexes with double strand DNA and anticancer drugs. Structural analysis revealed the presence of a methionine residues, Met762 and Met766, in the drug-binding pocket of hTop2α, allowing us to test whether a tighter Top2-drug association may be accomplished by introducing a methionine-directed, thioether-reactive Pt2+ into a drug to further stabilize the DNA break. To this end, we designed and obtained an organoplatinum compound, called etoplatin-N2β, by replacing the methionine-juxtaposing glycosidic group of etoposide with a cis-dichlorodiammineplatinum(II) moiety. Comparing to etoposide, etoplatin-N2β more potently inhibits the supercoil relaxation activity of hTop2α and hTop2β. While the Top2-mediated DNA breaks arrested by etoposide can be rejoined, the breaks produced in the presence of etoplatin-N2β are practically irreversible. Crystallographic analyses of hTop2α and hTop2β cleavage complex stabilized by etoplatin-N2β demonstrate the formation of a coordinate bond between Pt2+ and the Sδ atom of Met766 in the α-isoform and the equivalent Met782 in β-isoform. Notably, this highly stable coordinate tether can be loosened by disrupting the structural integrity of drug binding pocket with protein denaturant, suggesting that the Pt2+ coordination chemistry may allow the development of a potent enzyme inhibitor with protein conformation-dependent reversibility. Our results also implicate selective targeting of an hTop2α-specific methionine (Met762) may be achieved to suppress hTop2β-related side effects. | en |
dc.description.provenance | Made available in DSpace on 2021-05-19T17:49:00Z (GMT). No. of bitstreams: 1 ntu-106-D98442004-1.pdf: 8386223 bytes, checksum: 24e98bacefa851de7d11088a3e853d80 (MD5) Previous issue date: 2017 | en |
dc.description.tableofcontents | Contents
謝誌 ………………………………………………………… I 中文摘要 …...………………………………………….………. II Abstract ..……………………………………………………. IV Abbreviations ……………………………………………………… VI Contents .…………………………………………...……….. VII List of Figures ..………………………………....………………… IX List of Table and Scheme ……………………………………………………… XI 1. Introduction ....................................................................................................... 1 1.1. DNA Topoisomerase and DNA topology problem ................................... 2 1.2. Classification and function of DNA Topoisomerase ................................. 4 1.3. The structure and molecular mechanism of Type IIA topoisomerase ....... 6 1.4. Human type IIA topoisomerase ................................................................. 9 1.5. Type IIA topoisomerase poison and side effect ........................................ 10 1.6. Topoisomerase II-Mediated DNA Breaks by Site-Specific Pt(II)-Methionine Coordination Chemistry ........................................................................... 11 2. Method and Materials ..................................................................................... 14 2.1. Protein Purification .................................................................................. 15 2.2. DNA Substrate for Crystallography ......................................................... 19 2.3. Crystallization ......................................................................................... 19 2.4. Post-Crystallization Drug Replacement ................................................... 21 2.5. Data Collection and Structure Determine ................................................ 22 2.6. Protein assay ............................................................................................ 26 3. Results and Discussion ..................................................................................... 29 3.1. The structure of hTop2αcore-DNA-VM26 ternary complex .................. 30 3.2. Comparison hTop2αcore-DNA-VM26 and hTop2βcore-DNA-VM26 ........ 32 3.3. Structural analysis of hTop2α in complexes with other Top2-targeting agents (Epipodophyllotoxins、Anthraquinone) ..................................... 34 3.4. Rational for developing isoform-specific Top2-targeting agents ............. 36 3.5. Structure-based design of a hTop2-targeting organoplatinum compound . 38 3.6. Etoplatin-N2β potently inhibits the supercoil relaxation activity of human Top2 isoforms .......................................................................................... 39 3.7. The Top2-mediated DNA breaks arrested by etoplatin-N2S are practically irreversible .............................................................................................. 41 3.8. Crystallographic analysis of human Top2 isoforms in complexes with DNA and etoplatins .......................................................................................... 42 3.9. The coordinate tether between etoplatin-N2β and hTop2 exhibits a protein conformation-dependent reversibility ..................................................... 44 3.10. Etoplatin-N2β displays reduced reactivity toward DNA compared to cisplatin .................................................................................................................... 45 4. Conclusion ........................................................................................................ 47 5. Figures ............................................................................................................... 53 6. Tables and Scheme ........................................................................................... 84 7. References ......................................................................................................... 90 | |
dc.language.iso | en | |
dc.title | 抗癌藥物引發之人類第二型拓樸異構酶α亞型切割複合體之結構分析: 發展具亞型專一性之第二型拓撲異構酶標靶抗癌藥物 | zh_TW |
dc.title | Structural Studies of Human Topoisomerase IIα in Complexes with DNA and Anticancer Drugs : Development of Selective Topoisomerase II-Targeting Anticancer Drugs | en |
dc.type | Thesis | |
dc.date.schoolyear | 106-1 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 林敬哲(Jing-Jer Lin),李財坤(Tsai-Kun Li),李弘文(Hung-Wen Li),冀宏源(Hung-Yuan Chi) | |
dc.subject.keyword | 人類第二型拓樸異構?,拓樸異構?產生的 DNA 斷裂,鉑-硫配位鍵,有機鉑化合物,蛋白質構型依賴之可逆反應, | zh_TW |
dc.subject.keyword | human type II topoisomerases,topoisomerase-induced DNA break,platinum(II)-thioether coordination,organoplatinum compound,protein conformation-dependent reversibility., | en |
dc.relation.page | 96 | |
dc.identifier.doi | 10.6342/NTU201704200 | |
dc.rights.note | 同意授權(全球公開) | |
dc.date.accepted | 2017-09-11 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 生物化學暨分子生物學研究所 | zh_TW |
顯示於系所單位: | 生物化學暨分子生物學科研究所 |
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