我們利用核磁共振方法重新定出台灣眼鏡蛇心臟毒蛋白分子（CTX A3）在中性水溶液中的結構，接著利用碳十三的核磁共振弛緩實驗來進一步獲得有關分子的動態與結構的性質，分子骨架的秩序參數及整個分子翻轉速度在此被決定出來。分子在水溶液中是以進行等方向性的翻轉運動，同時翻轉時間約計在3.8到4.5奈秒之間。最近，心臟毒蛋白分子中的第二指環區被認為能夠與細胞膜產生重要的交互作用，而我們利用NOESY及ROESY光譜技術，成功鑑定出在CTX A3分子的第二指環區中，包含了一個結合水分子，為了了解這個水分子是否扮演著調控心臟毒蛋白分子與細胞膜結合的重要角色，氧十七的三量子核磁共振光譜及電腦模擬技術則被進一步使用來決定這顆水分子的動態性質。令人驚訝的是，結合水位在的第二指環區是一個具高度動態性質，同時也是一個易與外界水分子接觸的區域，而水分子竟仍能長時間的停留在第二指環區中，停留時間長達5 ns至100 ms。其原因被推測為結合水能與Met26的NH、Thr29的CO及Val32的CO產生穩定的氫鍵，進而能長時間的停留在第二指環區中。而在分析數種P型態的心臟毒蛋白分子後，我們亦針對具有結合水的第二指環區定出一段相同的氨機酸序列，為MxAxPxVPV。最後，結合水在第二指環區的進出速率，可能具有調控與細胞膜結合的功能。
對於一些位在細胞表面帶負電的醣胺素分子，也被認為是心臟毒蛋白可能的受體。而環聚在心臟毒蛋白凹面的一些帶正電荷的氨機酸，則被證實能與醣胺素有選擇性的結合。醣胺素其中一類的分子，醣肝素不只會促使心臟毒蛋白強烈聚集，同時能增強心臟毒蛋白對細胞膜的穿透能力。為了進一步了解心臟毒蛋白與醣肝素間的交互作用，我們先使用醣肝素的雙醣分子為材料，利用一維核磁共振選擇性激發光譜來研究與心臟毒蛋白的作用。藉由分子間NOE的訊號，我們推斷出雙醣分子反而是結合在心臟毒蛋白的凸面，接近Cys38的區域，藉此進而鑑定出醣肝素的另一個結合位置。同時我們也發現，雙醣分子在結合到毒蛋白表面後，單一醣分子的六碳環及雙醣間的鍵角也會有改變的情況，並且雙醣上帶負電硫酸根的位置及毒蛋白表面正電荷的分布，在兩者交互作用中扮演了重要的角色。我們也進一步了解到醣肝素如何利用兩個不同的結合位置促使心臟毒蛋白產生聚集的現象。

從自然界取得的醣肝素，其多醣分子都具有混合物的特性，其中包含許多具有不同硫酸根位置的醣分子，我們利用酵素分解取得的四醣分子亦同。我們接著善用一維核磁共振選擇性激發光譜其高解析度的優點，決定出醣肝素的四醣分子包含了三種主要的成分，其結構如下DUA2S-GlcNS6S-IdoA2S-GlcNS6S、DUA2S-GlcNS6S-GlcA-GlcNS6S及 DUA2S-GlcNS6S-IdoA2S-GlcNS。鑒於在一維光譜中，各個成分的訊號相當清晰可分辨，所以我們進一步決定出能與心臟毒蛋白有較強結合能力的四醣分子，藉由分析醣分子六碳環上第一個氫原子遲緩時間的改變，我們認為具有完全硫酸化的四醣分子與心臟毒蛋白能有較強的結合能力。同時我們亦提出，可以在不經過傳統生化純化的步驟下，直接利用一維核磁共振選擇性激發光譜，從四醣混合物中解出單一四醣分子與心臟毒蛋白的複合結構。

最後，在於醣肝素能增強心臟毒蛋白對細胞膜結合的問題上，我們嘗試利用脫脂酸磷脂質組成的微胞小球作為模型來研究這個問題。由光譜獲得的證據，顯示醣肝素的六醣分子可以促使心臟毒蛋白在指環區產生細微的結構變化，讓分子變為更容易與細胞膜作用。而NOE及霍氏紅外線光譜指出，心臟毒蛋白在結合到六醣分子或脫脂酸磷脂質後，結構的轉變是類似的，而這其中似乎包含了疏水性指環區及b平板間結構的微妙連結。這是個首次提及，親水性醣分子如何藉由改變雙性蛋白分子的結構來增強與疏水性脂質結合的例子。透過相同的機制，類似的三體交互作用，可能會在一般的細胞表面發生。

Solution NMR structure of CTX A3 from Taiwan cobra (Naja atra) was determined at neutral pH by conventional 2D 1H NMR techniques. The molecular dynamics investigated using a model-free analysis of the 13C NMR spin-lattice relaxation experiments to help understanding of the relationship between structure and motional property. The order parameter (S2) of the polypeptide backbone and overall correlation time (tR) of the relatively flat CTX A3 are presented. As estimated by 13C NMR relaxation, overall tumbling motion of CTX A3 molecule can be concluded to be isotropic with a correlation time of about 3.8 - 4.5 ns. Recent studies of cobra P-type CTXs have shown that the loop II plays a crucial role in binding to biological membranes. A bound water molecule was then identified in the interior of loop II in CTX A3 by 1H NOESY/ROESY. In order to understand the role of bound water in the loop, the dynamics of the bound water was determined by a comprehensive analysis of 17O transverse triple-quantum filtered NMR and computer simulation. The single water molecule was found to be tightly hydrogen bonded to the NH of Met26, CO of Thr29 and CO of Val32. Surprisingly, despite the relatively long residence time (from 5 ns to 100 ms), the bound water molecule of CTX A3 is located within a dynamic (S2 ~ 0.7) and solvent accessible loop. Comparing to several P-type CTXs, the consensus sequence of MxAxPxVPV was derived. It is proposed that the exchange rate of the bound water may play a role in regulating the lipid binding mode of amphiphilic CTX molecules.
Glycosaminoglycans (GAGs) have also been suggested to be another potential target for CTX with high affinity and specificity via a cationic belt at the concave surface of the polypeptide. The interaction of GAGs, such as high molecular weight heparin, with CTXs can not only induce aggregation of CTX molecules but also enhance their penetration into membranes. Aiming to understand the interaction of CTXs and heparin, the binding of short chain heparin-derived disaccharide to CTX A3 was investigated by proton 1D NMR selective methods first. A novel heparin binding site on the convex side of the CTX, near the rigid disulfide-bond tightened core region of Cys38, was then identified due to the observation of intermolecular NOEs between protein and carbohydrate. The derived carbohydrate conformation indicated that the glycosidic linkage and the ring conformation change upon binding to CTX A3. Specifically, comparative studies of several heparin disaccharide homologues with CTX Tg and CTX A3 indicated that the electrostatic interaction between different sulfation pattern and Lysine residues played an important role on binding. These results also suggest a model on how the CTX-heparin interaction may regulate heparin-induced aggregation of the toxin via the second heparin binding site.

Although the bound form conformation of heparin disaccharide to cobra cardiotoxin has been determined, it remains a challenging issue to perform a similar study on heparin with longer chain length. Heparin-derived polysaccharide of biological origin is heterogeneous with different sulfation patterns and difficult to purify by using chromatographic method. The 1H NMR signals of long chain heparin are also difficult to resolve since they are severely overlapping to each other. Herein, we demonstrate that 1D selective excitation methods may have an advantage in studying a mixture of heparin-derived tetrasaccharide and their interaction with cobra cardiotoxin. A complete assignment of 1H NMR signal for three major tetrasaccharides, i.e., DUA2S-GlcNS6S-IdoA2S-GlcNS6S, DUA2S-GlcNS6S-GlcA-GlcNS6S and DUA2S-GlcNS6S-IdoA2S-GlcNS is demonstrated for the first time by using 1D selective excitation experiment. In addition, by comparing the relaxation time of the selectively excited anomeric proton in the absent and present of CTX A3, we concluded that the component with fully sulfation pattern owns the highest affinity with CTX A3.

By taking lysophosphatidylcholine (LPC) micelles as a membrane model, we have shown that the binding of heparin-derived hexasaccharide (Hep-6) to CTX at the b-strand region can induce conformational changes of CTX near its membrane binding loops and promote the binding activity of CTX towards to LPC. The Fourier-transform infrared spectra and NOE values of Hep-6/CTX and CTX/LPC complex in aqueous buffer also supplemented the aforementioned observation. So the detected conformational change may presumably be due to the result of structural coupling between the connecting loops and its b-strands. This is the first documentation of results showing how the association of hydrophilic carbohydrate molecules with amphiphilic proteins can promote hydrophobic protein-lipid interaction via the stabilization of its membrane bound form. A similar mechanism involving tripartite interactions of heparin, protein, and lipid molecules may be operative near the extracellular matrix of cell membranes.

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