t-PA K1区的同源模建及Kringle区与Lysine相互作用的研究  

Homology Modeling of Tissue type Plasminogen Activator K1 Domain and Studies on the Interactions Between Kringles and Lysine

作　　者：王国力[1] 刘士辉[1] 徐秀英 黄培堂[1] 黄翠芬[1] 

机构地区：[1]北京生物工程研究所

出　　处：《生物工程学报》1998年第1期20-27,共8页Chinese Journal of Biotechnology

基　　金：全军医药卫生科研基金

摘　　要：利用同源模建方法预测了ｔＰＡＫ１区的三维结构。通过结构叠合确定了ｔＰＡＫ１、Ｋ２区，纤溶酶原Ｋ１、Ｋ４区及ＵＫＫ区的Ｌｙｓｉｎｅ结合口袋。静电势计算及疏水性分析表明，在ｔＰＡＫ２区以及纤溶酶原Ｋ１、Ｋ４区与纤维蛋白裸露的Ｌｙｓｉｎｅ之间存在明显的静电势互补和疏水面契合。确定了影响Ｋｒｉｎｇｌｅ区结合口袋与Ｌｙｓｉｎｅ亲和的重要氨基酸，分析了ｔＰＡＫ１区、ＵＫＫ区不能结合Ｌｙｓｉｎｅ的原因，由此设计了具有Ｌｙｓｉｎｅ亲和力的新型ｔＰＡＫ１区及ＵＫＫ区突变体。利用模拟残基突变技术预测了突变体的结构变化，分析了突变后ｔＰＡＫ１区及ＵＫＫ区与Ｌｙｓｉｎｅ亲和力的变化，初步在理论上肯定了设计方案的合理性。The 3 D structure of t PA K1 domain are predicted by the method of homology modeling.The putative lysine binding pockets of t PA K1,UK K,PLG K1 and K4 are determined by superposing their 3 D structures to that of t PA K2 domain,of which the lysine binding pockets have been revealed previously.After that the key residues of lysine binding pockets of kringles are identified.The structural analyses show that both of the electrostatic potential and hydrophobic complementarity are well matched between lysine and binding pockets of t PA K2,PLG K1 and K4,but for t PA K1 and UK K domains the complementarity do not matched well in one or both of the respects.It is proposed that this is the reason that t PA K1 and UK K domains do not bear the ability of binding lysine.With the respect of improving the affinity for fibrin,new type mutants of t PA K1 and UK K domain are designed,and structural changes caused by mutation are predicted by simulating the residue replacements.The mutant structural models demonstrate that the molecular design are reasonable.

关 键 词：同源模建 计算机 Kringle区 血栓 溶栓剂 

分 类 号：R973.2[医药卫生—药品]