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利用分子動力學模擬計算討論GSK3β-GSKIP及Keap1-Nrf2 ...

國立高雄大學生物科技研究所

利用分子動力學模擬計算討論GSK3β-GSKIP及Keap1-Nrf2 兩組蛋白質作用模式 = Molecular Dynamics Simulations on the Binding Modes of GSK3β-GSKIP and Keap1-Nrf2

紀錄類型:	書目-語言資料,印刷品 : 單行本
並列題名:	Molecular Dynamics Simulations on the Binding Modes of GSK3β-GSKIP and Keap1-Nrf2
作者:	羅振維,
其他團體作者:	國立高雄大學
出版地:	[高雄市]
出版者:	撰者;
出版年:	民99[2010]
面頁冊數:	109面圖，表 : 30公分;
標題:	分子動態模擬
標題:	Molecular Dynamics Simulation
電子資源:	http://handle.ncl.edu.tw/11296/ndltd/33537854984865154537
摘要註:	蛋白質的功能需經由數個蛋白質之間的交互作用後方能表現，因此了解蛋白質間的交互作用可視為研究功能性基因體學與蛋白質體學的起始課題。一般以分子生物實驗探討蛋白質作用能了解巨觀現象，而分子動態模擬(molecular dynamics simulation)藉由解釋蛋白質原子層級交互作用之動態行為能更深入了解蛋白質機制。本研究即是利用分子動態模擬方法探討兩組訊息傳遞機制系統中蛋白質間的作用模式，分別是GSK3β-GSKIP 及Keap1-Nrf2 間交互作用。GSKIP 藉由與GSK3β結合而促進β-catenin 下游基因轉換，過度活化此機制將導致癌症的生成，其結合模式目前尚未有相關構型探討，本論文第一部份即以分子動態模擬建構GSK3β與GSKIP 結合模式。GSK3β主要用一段α-helix 及loop 以疏水性作用結合GSKIP，此外GSK3β上D264 所能形成之靜電作用對於兩蛋白質結合也是不可或缺之作用力，其中V267G 點突變已由文獻研究證實會使兩蛋白質無法結合但Y288F 則否。本論文並以點突變分子動態模擬解釋兩組點突變對蛋白質結合影響，並另進行D264A 點突變探討D264 對蛋白質結合之重要性。建立的GSKIP 結合構型並與GSK3β-AxinGID及GSK3β-FRATide 比較，以討論三種胜肽結合差異，由分析比對可知GSKIP 與AxinGID會有較相近之結合模式。Keap1 藉由與Nrf2 結合以抑制生物體內抗氧化作用機制，當Nrf2 過度被抑制將使細胞長期處於被氧化物攻擊的環境而易導致病變引發癌症生成，由文獻研究已證實Keap1 上R415A、Y572A，Nrf2 上T80A 點突變及Keap1 蛋白質在缺失CTR domain 時將導致兩蛋白質無法結合。本論文第二部份以分子動態模擬方式探討這些突變相對於WT 型態蛋白質結合影響；此外，由分析WT 作用可知Nrf2 上E79 對兩蛋白質提供重要作用，因此同樣進行E79A 點突變之動態模擬探討。由模擬結構知在R415A、Y572A及E79A 造成兩蛋白質結合之疏水及靜電作用力消失進而影響兩蛋白質結合；Nrf2 上T80A 點突變及Keap1 上CTR domain 缺失則分別改變Nrf2 及Keap1 構型致使兩蛋白質無法結合。本論文所得的蛋白質結合構型結論將提供於未來藥物發展並期望能對生理機制進一步調控以達疾病治療。 Molecular dynamics (MD) simulations have long been recognized as a useful tool in providing atomic level details on interpretation of biomolecular experimental observations. In this study we applied MD simulations to investigate the protein-protein interaction of two systems, namely, GSK3β-GSKIP and Keap1-Nrf2, and compared our findings with experimental data from literatures. GSKIP is a newly discovered protein interacting with GSK3β, that participates in a number of signal transduction pathways related to the cancers. In the first part of this thesis, we determined the binding mode between GSK3β and a peptide derived from GSKIP. Based on the complex structure, we studied three mutant systems, including D264A, V267G, andY288F, to explain the roles of these three amino acids on GSK3β in accommodating GSKIP, as pointed out earlier. Meanwhile, the determined GSK3β−GSKIP complex structure was compared with two other known complexes, GSK3β−AxinGID and GSK3β−FRATide, which are essential in WNT signal transduction pathway. Our results showed that all these three peptides share a common motif, L(A)-X-X-R-L, and reside in the same groove in GSK3β. Our modeling result suggests that GSK3β−GSKIP behaves similar to GSK3β−AxinGID.The second part of this thesis focuses on Keap1 and a peptide derived from Nrf2, a protein in response to the cellular oxidative stress. In the circumstance of no stress, Keap1 represses Nrf2. In clinical research it was demonstrated that their interaction is abolished by a number of single point mutations such as R415A and Y572A in Keap1, and T80A in Nrf2. Deletingthe CTR domain in Keap1 also fails the complex formation. Herein, we studied the wild type and the above-mentioned mutants to provide unbinding mechanisms upon mutations. We also revealed the cause of unbinding due to the CTR deletion. Interestingly, we found that Nrf2’s T80 does not contribute greatly in associating with Keap1 but plays a pivotal role in maintaining the peptide in a perfect anti-parallel β strand conformation to fit in the Keap1binding surface.

利用分子動力學模擬計算討論GSK3β-GSKIP及Keap1-Nrf2 兩組蛋白質作用模式 = Molecular Dynamics Simulations on the Binding Modes of GSK3β-GSKIP and Keap1-Nrf2
羅, 振維

利用分子動力學模擬計算討論GSK3β-GSKIP及Keap1-Nrf2 兩組蛋白質作用模式 = Molecular Dynamics Simulations on the Binding Modes of GSK3β-GSKIP and Keap1-Nrf2 / 羅振維撰 - [高雄市] : 撰者, 民99[2010]. - 109面 ; 圖，表 ; 30公分.
參考書目：面.
分子動態模擬Molecular Dynamics Simulation

利用分子動力學模擬計算討論GSK3β-GSKIP及Keap1-Nrf2 兩組蛋白質作用模式 = Molecular Dynamics Simulations on the Binding Modes of GSK3β-GSKIP and Keap1-Nrf2
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330 $a 蛋白質的功能需經由數個蛋白質之間的交互作用後方能表現，因此了解蛋白質間的交互作用可視為研究功能性基因體學與蛋白質體學的起始課題。一般以分子生物實驗探討蛋白質作用能了解巨觀現象，而分子動態模擬(molecular dynamics simulation)藉由解釋蛋白質原子層級交互作用之動態行為能更深入了解蛋白質機制。本研究即是利用分子動態模擬方法探討兩組訊息傳遞機制系統中蛋白質間的作用模式，分別是GSK3β-GSKIP 及Keap1-Nrf2 間交互作用。GSKIP 藉由與GSK3β結合而促進β-catenin 下游基因轉換，過度活化此機制將導致癌症的生成，其結合模式目前尚未有相關構型探討，本論文第一部份即以分子動態模擬建構GSK3β與GSKIP 結合模式。GSK3β主要用一段α-helix 及loop 以疏水性作用結合GSKIP，此外GSK3β上D264 所能形成之靜電作用對於兩蛋白質結合也是不可或缺之作用力，其中V267G 點突變已由文獻研究證實會使兩蛋白質無法結合但Y288F 則否。本論文並以點突變分子動態模擬解釋兩組點突變對蛋白質結合影響，並另進行D264A 點突變探討D264 對蛋白質結合之重要性。建立的GSKIP 結合構型並與GSK3β-AxinGID及GSK3β-FRATide 比較，以討論三種胜肽結合差異，由分析比對可知GSKIP 與AxinGID會有較相近之結合模式。Keap1 藉由與Nrf2 結合以抑制生物體內抗氧化作用機制，當Nrf2 過度被抑制將使細胞長期處於被氧化物攻擊的環境而易導致病變引發癌症生成，由文獻研究已證實Keap1 上R415A、Y572A，Nrf2 上T80A 點突變及Keap1 蛋白質在缺失CTR domain 時將導致兩蛋白質無法結合。本論文第二部份以分子動態模擬方式探討這些突變相對於WT 型態蛋白質結合影響；此外，由分析WT 作用可知Nrf2 上E79 對兩蛋白質提供重要作用，因此同樣進行E79A 點突變之動態模擬探討。由模擬結構知在R415A、Y572A及E79A 造成兩蛋白質結合之疏水及靜電作用力消失進而影響兩蛋白質結合；Nrf2 上T80A 點突變及Keap1 上CTR domain 缺失則分別改變Nrf2 及Keap1 構型致使兩蛋白質無法結合。本論文所得的蛋白質結合構型結論將提供於未來藥物發展並期望能對生理機制進一步調控以達疾病治療。 Molecular dynamics (MD) simulations have long been recognized as a useful tool in providing atomic level details on interpretation of biomolecular experimental observations. In this study we applied MD simulations to investigate the protein-protein interaction of two systems, namely, GSK3β-GSKIP and Keap1-Nrf2, and compared our findings with experimental data from literatures. GSKIP is a newly discovered protein interacting with GSK3β, that participates in a number of signal transduction pathways related to the cancers. In the first part of this thesis, we determined the binding mode between GSK3β and a peptide derived from GSKIP. Based on the complex structure, we studied three mutant systems, including D264A, V267G, andY288F, to explain the roles of these three amino acids on GSK3β in accommodating GSKIP, as pointed out earlier. Meanwhile, the determined GSK3β−GSKIP complex structure was compared with two other known complexes, GSK3β−AxinGID and GSK3β−FRATide, which are essential in WNT signal transduction pathway. Our results showed that all these three peptides share a common motif, L(A)-X-X-R-L, and reside in the same groove in GSK3β. Our modeling result suggests that GSK3β−GSKIP behaves similar to GSK3β−AxinGID.The second part of this thesis focuses on Keap1 and a peptide derived from Nrf2, a protein in response to the cellular oxidative stress. In the circumstance of no stress, Keap1 represses Nrf2. In clinical research it was demonstrated that their interaction is abolished by a number of single point mutations such as R415A and Y572A in Keap1, and T80A in Nrf2. Deletingthe CTR domain in Keap1 also fails the complex formation. Herein, we studied the wild type and the above-mentioned mutants to provide unbinding mechanisms upon mutations. We also revealed the cause of unbinding due to the CTR deletion. Interestingly, we found that Nrf2’s T80 does not contribute greatly in associating with Keap1 but plays a pivotal role in maintaining the peptide in a perfect anti-parallel β strand conformation to fit in the Keap1binding surface.
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