摘要
在生物系統中的許多蛋白質有其獨特的作用區域，可與特定的分
子結合，而且這些交互作用會決定蛋白質的活性與功能。研究蛋白質
與分子的交互作用有助於了解蛋白質在生物系統中如何發揮其功
能。這些作用的分子(統稱為ligands)包含蛋白、胜肽、核酸、金屬離
子及藥物等等…。本篇論文進行兩個研究案例，分別是蛋白與藥物之
交互作用以及蛋白與胜肽之交互作用。
在研究案例一中，我們從結構上來討論hEGF 與suramin 之交互
作用。人類表皮生長因子(hEGF)可促使多種生物細胞(包括腫瘤細胞)
的增生分化，而此生物活性是透過hEGF與細胞膜表面上的特定受體
(hEGFR)結合進而誘導產生一系列訊息傳導所致。Suramin
(polysulfonated naphthylurea)作為生長因子阻斷劑，可以抑制非小細胞
肺癌腫瘤細胞(NSCLC，其細胞表面大量表現hEGFR)之細胞增生能
力。我們利用等溫滴定量熱法及核磁共振技術解析hEGF蛋白在生理
條件水溶液中的結構並觀測hEGF 與suramin 的交互作用。本篇論文
中提出的hEGF 水溶液結構與已發表之2:2 EGF–EGFR 複合物中的
hEGF 結構在C 端有明顯不同，未和hEGFR 複合之hEGF 水溶液結
構在C端形成一個疏水性基團。由這樣的構型差異推論：當hEGF與
hEGFR結合，hEGF本身會產生構型變化，解開其C端的疏水性基團
以利於受體之結合。有趣的是，根據我們解出的hEGF-suramin 複合
體結構，suramin 正好也是結合在hEGF 的C 端(Arg45 周圍)，可以
保護C端的疏水性基團，因而阻斷了hEGF和hEGFR的結合。
在研究案例二中，我們解出了HB-EGF-CT和mBAG-1-UBH的複
合物結構並討論兩者間的結合區域。BCL2-associated athanogene 1
(BAG-1)是一個重要的調節蛋白，可與多種抑制細胞凋亡相關之訊息
分子結合。老鼠BAG-1 的ubiquitin 類似區域(簡稱mBAG-1-UBH)由
97 個胺基酸所組成，已被證實可與proHB-EGF存在細胞質中的尾端
(簡稱HB-EGF-CT)交互作用，且此作用具有重要的生物意義 (即為兩
蛋白對細胞存活的協同作用)。本篇論文中，我們對mBAG-1-UBH和
HB-EGF-CT 進行主鏈和支鏈上各原子的化學位移判定並且進行結構
計算。我們利用等溫滴定量熱法及二維、三維核磁共振技術(1H-15N
HSQC滴定和13C-filter NOESY)來決定此交互作用之結合強度以及結
構上的結合區域。HB-EGF-CT在mBAG-1-UBH結構上的結合位置位
於其C 端及12 之間的轉折區域。HB-EGF-CT 摺疊成環狀結構(不
具任何二級結構)，用兩端(N和C端)來和mBAG-1-UBH 作用。兩蛋
白間的作用力包含疏水性、正負電荷及靜電作用力。

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