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研究生:吳承軒
研究生(外文):Wu, Cheng-Hsuan
論文名稱:白血球介素1受體蛋白激酶1構型差異與選擇性抑制劑篩選及結合機制
論文名稱(外文):Configurational differences and binding mechanisms of Interleukin-1 receptor-associated kinase 1
指導教授:楊進木
指導教授(外文):Yang, Jinn-Moon
口試委員:楊登傑鄒協成許凱程楊進木
口試委員(外文):Yang, Deng-JyeTzou, Shey-CherngHsu, Kai-ChengYang, Jinn-Moon
口試日期:2020-07-22
學位類別:碩士
校院名稱:國立交通大學
系所名稱:生物科技學系
學門:生命科學學門
學類:生物科技學類
論文種類:學術論文
論文出版年:2020
畢業學年度:108
語文別:中文
論文頁數:57
中文關鍵詞:白血球介素1受體蛋白激酶1蛋白質激酶抑制劑選擇性抑制劑
外文關鍵詞:Interleukin-1 receptor-associated kinaseIRAK1IRAK4kinase inhibitors
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白細胞介素1受體相關激酶1(Interleukin-1 receptor-associated kinase 1,IRAK1)參與在調節類鐸受體(Toll-like receptor)訊號途徑的下游及對於先天性免疫、炎性疾病和癌症等相關疾病至關重要。透過癌症基因表現圖譜分析,IRAK1在許多癌症中高表現,並與癌症轉移相關。且已有文獻指出透過抑制IRAK1降低其下游產物的表達,將有助於疾病的治療,例如:紅斑性狼瘡(systemic lupus erythematosus)、肝纖維化(liver fibrosis)及三陰性乳癌(triple-negative breast cancer,TNBC)等疾病,因此開發針對IRAK1為標靶的專一抑制劑為重要的議題。然而,目前卻沒有任何針對IRAK1為標靶的核准藥物,現有IRAK1抑制劑大多對同源蛋白IRAK4也缺乏選擇性。此外,結構藥物設計高度依賴於蛋白質的三維結晶結構,缺乏結構可能會減緩藥物發展與藥物優化,IRAK1可能因其蛋白質的不穩定性,至今仍只有一個結晶結構。為了解決這些問題,本研究提出利用同源蛋白IRAK4的結構豐富性,探索IRAK1的構型多樣性的方法,將有利於IRAK1的抑制劑設計及對於缺乏蛋白質結構提出藥物設計的解決方案。利用配體-結晶複合物交互作用力將45個IRAK4結晶結構分群,結果顯示IRAK1亦可能具有多種結構類型,並依其配體結合方向分為四種類型,分為Type-CL(向c-lobe左側延伸),Type-CR(向c-lobe右側延伸),Type-A(ATP結合區域)和Type-N(向n-lobe延伸)。四類型均顯示IRAK特殊結構改變以及與配體獨特的結合環境,並且利用序列一致性、結構與配體-蛋白質交互作用力相似及配體相似的抑制活性三個分析構面驗證IRAK1的結構多樣性。我們模擬出四種類型的IRAK1構型,除了提供IRAK1不同的藥物開發策略外,發現了IRAK1具有Type-N的構型,並且發現舊藥Drug Y為IRAK1潛在選擇性抑制劑,根據激酶抑制活性試驗結果顯示,其對IRAK1(IC50〜93 nM)的效力相較IRAK4(IC50> 10 uM)好百倍以上。最後,發現Q262、F266與G357為造成選擇性的關鍵胺基酸。本研究不僅為第一個提出IRAK1結構多樣性,亦提供藥物開發嶄新的機會,並且相信我們的方法為設計針對特定激酶家族的選擇性抑製劑提供了有用的策略。
Interleukin-1 receptor-associated kinase 1 (IRAK1) is crucial to regulate downstream of Toll-like receptor signalling pathway and is involved in innate immune, inflammatory diseases and cancers. The inhibition of IRAK1 in turn downregulation of downstream helps the treatment for diseases such as systemic lupus erythematosus, liver fibrosis ,and triple-negative breast cancer (TNBC). There is an emergency task for developing inhibitors for targeting IRAK1. However, there are currently no approved drugs targeting IRAK1, and existing IRAK1 inhibitors mainly lack selectivity for the homologous protein IRAK4. In addition, structural drug design is highly dependent on the three-dimensional crystal structure of the protein. The structural deficiency often obstacle drug development and optimization. In present, human IRAK1 is only presented in one crystal structure because its degraded into two fragments that difficult to form any crystals. To address these issues, this study proposes a method to explore IRAK1 structural elasticity and to prospect the binding mechanisms for designing its inhibitors by utilizing abundant homologous protein IRAK4 structures. Our results show that IRAK1 should have four configuration types, including Type-CL (left of c-lobe), Type-CR (right of c-lobe), Type-A (ATP site), and Type-N (n-lobe), according to classify ligand-protein interactions profile of 45 IRAK4-ligand complexes. Four type shows the distinct binding environment and conformation difference between IRAK1, then we validated the structural diversity of IRAK1 using three analytical planes: sequence identity, similar structure and ligand-protein interaction, and similar inhibition of ligands. We simulated four types of IRAK1 not only providing different drug development strategies for IRAK1 but also discovering new potent IRAK1 type-N inhibitor, Drug Y, FDA approved drug. It is 100 times more potent for IRAK1 (IC50 ~93 nM) than for IRAK4 (IC50 >10 uM) based on our kinase inhibition assay. Finally, it was found that Q262, F266 and G357 are the key residues that cause selectivity. We propose the configurational flexibility and selectivity residues of IRAK1 and believe that our approach provides a useful strategy for designing selective inhibitors for a specific kinase family.
中文摘要 I
ABSTRACT II
致謝 III
目錄 IV
圖目錄 VI
表目錄 VIII
第1章、 緒論 1
1.1. 研究背景 1
1.1.1 蛋白質激酶 1
1.1.2 蛋白質激酶藥物選擇性 6
1.1.3 IRAK1選擇性抑制劑Drug X 8
1.2. 研究動機 13
1.3. 論文總覽 15
第2章、 研究方法及使用材料 16
2.1. 方法論策略概述 16
2.2. 使用材料與資料之準備 16
2.3. 分析結構構型改變 18
2.4. 計算配體化合物相似性 18
2.5. IRAK1結構模擬 18
2.6. 分子對接與作用力分析 19
2.7. 蛋白質結合位點-化合物官能基之地圖 19
2.8. 化合物抑制活性測定 19
第3章、 成果與討論 20
3.1. 分析IRAK結構差異 20
3.1.1 模板蛋白之挑選 20
3.1.2 IRAK 4種構型 23
3.1.3 IRAK構型差異 27
3.1.4 IRAK結合機制 30
3.2. IRAK1有與IRAK4相似之構型 32
3.2.1 IRAK1與IRAK4序列相似 32
3.2.2 IRAK1及IRAK4在結相同配體時具有類似的結構及作用力 33
3.2.3 IRAK4配體對IRAK1有類似的抑制活性 36
3.2.4 利用分子對接模擬IRAK1與配體結合 38
3.2.5 Type-N配體抑制IRAK1 40
3.3. IRAK1抑制劑對IRAK1選擇性 42
3.3.1 Drug Y選擇性抑制劑 42
3.3.2 Drug X選擇性抑制劑 46
第4章、 結論 50
4.1. 總結 50
4.2. 未來展望 51
參考文獻 52
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