Engh R A, Wright H T, Huber R
Max Planck Institut für Biochemie, Martinsried bei München, FRG.
Protein Eng. 1990 May;3(6):469-77. doi: 10.1093/protein/3.6.469.
The structure of the intact form of the serpin alpha 1-proteinase inhibitor has been modeled based on the assumption that the central strand s4A of the six-stranded beta-sheet A of the cleaved inhibitor is not incorporated into the sheet of intact alpha 1-proteinase inhibitor. This strand was removed from its position in the center of the sheet by suitable rotations about the backbone dihedrals of Lys343 using molecular graphics. The resulting structure was then annealed using molecular dynamics (MD) while applying progressive distance restraints to the reactive peptide bond (Met358-Ser359) for 50 ps. During this time, the disrupted beta-sheet reformed to create a five-stranded beta-sheet with strands 3 and 5 in a parallel arrangement. This change and accompanying structural rearrangements are largely confirmed by the X-ray structure of plakalbumin, whose structure reflects the overall structure of intact serpins. The successful modeling experiment demonstrates the utility of MD for making gross structural predictions based on related structures. The binding loop of the intact form is modeled to allow docking with serine proteinases, in particular thrombin, which most highly constrains the possible conformations of the binding loop.
丝氨酸蛋白酶抑制剂α1-抗胰蛋白酶完整形式的结构已基于以下假设进行建模：裂解抑制剂的六链β-折叠A的中央链s4A不并入完整α1-抗胰蛋白酶的折叠中。使用分子图形学通过围绕Lys343的主链二面角进行适当旋转，将该链从其在折叠中心的位置移除。然后使用分子动力学（MD）对所得结构进行退火，同时对反应性肽键（Met358-Ser359）施加渐进距离限制，持续50皮秒。在此期间， disruptedβ-折叠重新形成，形成一个五链β-折叠，其中链3和链5呈平行排列。 plakalbumin的X射线结构在很大程度上证实了这种变化和伴随的结构重排，其结构反映了完整丝氨酸蛋白酶抑制剂的整体结构。成功的建模实验证明了MD在基于相关结构进行总体结构预测方面的实用性。完整形式的结合环被建模以允许与丝氨酸蛋白酶，特别是凝血酶对接，凝血酶对结合环的可能构象限制最大。
