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本文运用X射线分析技术,在2分辨率测定了Arg-B31-人胰岛素(ABHI)四锌晶型的晶体结构,最后的晶体学R因子为0.189,模型的平均键长偏差为0.018。精化后的结构模型显示,ABHI分子B链羧端构象比天然分子更加稳定,在二聚体内,分子Ⅰ的Arg-B31与分子Ⅱ的Glu-B21之间形成一对新的侧链间离子键,从而在ABHI六聚体表面增加了三对由相邻分子间形成的次级键。ABHI是一种长效胰岛素,上述结构特征揭示了其长效性的主要结构基础:由于Arg-B31的引入使ABHI六聚体增加了三对离子键,从而使其解聚成单体的速率减慢,在体内形成一个持续供应“库”。由此,作用时效得以延长,产生长效特征。这一实验结果证实了作者关于“增加次级键,稳化寡聚体”以产生长效胰岛素的分子设计原理的正确性,以及通过模型拟合和能量优化对ABHI主要结构特征的预测。
In this paper, the crystal structure of Arg-B31-human insulin (ABHI) was determined by X-ray analysis. The final crystallographic R factor was 0.189, and the average bond length deviation of the model was 0.018. The refined structural model shows that the B-terminal carboxyl terminal conformation of ABHI molecule is more stable than that of native molecule. In dimer, a new pair of side-chain ions are formed between Arg-B31 of molecule I and Glu-B21 of molecule II Bond, thereby adding to the ABHI hexamer surface three pairs of secondary bonds formed between adjacent molecules. ABHI is a long-acting insulin. The above structural features reveal the major structural basis of its long-term effectiveness: the rate of depolymerization to monomer is slowed by the addition of three pairs of ABH hexamers resulting from the introduction of Arg-B31 , In the body to form a continuous supply “library.” As a result, the role of aging can be extended to produce long-term characteristics. This experimental result confirms the authors’ correctness of the molecular design principles of “increasing secondary bonds, stabilizing oligomers” to produce long-acting insulin, as well as predicting the major structural features of ABHI through model fitting and energy optimization.