Wang G, Liu S, Xu X, Huang P, Huang C
Beijing Institute of Biotechnology, China.
Chin J Biotechnol. 1998;14(1):17-24.
The 3-D structure of t-PA K1 domain was predicted by the method of homology modeling. The putative lysine-binding pockets of t-PA K1, UK K, PLG K1 and K4 were determined by superimposing their 3-D structures to that of t-PA K2 domain, of which the lysine-binding pockets had been revealed previously. After that the key residues of lysine-binding pockets of kringles were identified. The structural analyses showed that both the electrostatic potential and hydrophobic complementarity were well matched between lysine and the binding pockets of t-PA K2, PLG K1 and K4, but for t-PA K1 and UK K domains the complementarity did not match well in one or both respects. It is proposed that this is the reason that t-PA K1 and UK K domains do not bear the ability to bind lysine. With the respect of improving the affinity for fibrin, new types of mutants of t-PA K1 and UK K domains were designed, and structural changes caused by mutation were predicted by simulating the residue replacements. The mutant structural models demonstrated that the molecular design was reasonable.
采用同源建模方法预测了组织型纤溶酶原激活剂（t-PA）K1结构域的三维结构。通过将t-PA K1、尿激酶（UK）K、纤溶酶原（PLG）K1和K4的三维结构与先前已揭示赖氨酸结合口袋的t-PA K2结构域的三维结构进行叠加，确定了它们假定的赖氨酸结合口袋。之后确定了kringle结构域赖氨酸结合口袋的关键残基。结构分析表明，赖氨酸与t-PA K2、PLG K1和K4的结合口袋之间的静电势和疏水互补性均匹配良好，但对于t-PA K1和UK K结构域，在一个或两个方面的互补性匹配不佳。有人提出，这就是t-PA K1和UK K结构域不具备结合赖氨酸能力的原因。在提高对纤维蛋白亲和力方面，设计了新型的t-PA K1和UK K结构域突变体，并通过模拟残基替换预测了突变引起的结构变化。突变体结构模型表明分子设计是合理的。
