Structural study of an active analog of EX-4 in solution and micelle associated states.
Structural study of an active analog of EX-4 in solution and micelle associated states.
复制标题
EX-4 活性类似物在溶液和胶束相关状态下的结构研究。
作者：
Shuo Wang;Jiayi Yu;Wei Li;Fei Li
在许多设计用于治疗II型糖尿病的候选药物中，一种exendin-4 （EX-4）类似物被发现具有延长生物半衰期、增加细胞增殖和显著改善降低血糖的作用，这种类似物由β - asp取代Glu3和tyr取代EX-4的Glnl3而成。在本研究中，我们采用CD和NMR方法表征了该活性EX-4类似物在水、三氟乙醇（TFE）水溶液和十二烷基磷脂胆碱（DPC）胶束中的结构，并将其与EX-4类似物的结果进行了比较。两种EX-4肽均采用α -螺旋结构，n端无序，c端折叠成疏水簇。然而，模拟物在n端部分的螺旋延伸比EX-4长。螺旋旋转的增加可能有利于对胰高血糖素样肽-1受体胞外结构域的亲和力和对受体跨膜结构域关键n端残基的准确定位。模拟物比原生EX-4具有更强的聚合倾向，这是由于模拟物中的线圈相互作用比原生类型中更多。我们还研究了EX-4及其类似物与DPC胶束的关联，并观察到胶束诱导的两种肽插入，其N端和c端以及中心部分嵌入胶束，Asp9附近的残基和Trp25-Ser32周围的残基暴露更多的水。在分析这些结果的基础上，提出了一种单步配体-受体结合模型。
Of many drug candidates designed for treatment of type II diabetes, an exendin-4 (EX-4) analog from the substitutions of both beta-Asp for Glu3 and Tyrfor Glnl3 of EX-4 was found to have a prolongation in biological half life, an increase in cell proliferation and a remarkable improvement in reducing blood glucose with respect to EX-4. In this study, we applied CD and NMR approaches to characterize the structures of this active EX-4 analog in water, trifluoroethanol (TFE) aqueous solution, and dodecylphosphocholine (DPC) micelles and compared the results of the EX-4 analog with those of EX-4. Both EX-4 peptides adopt alpha-helix structures with the N-termini disordered and the C-terminal parts folded as hydrophobic clusters in these media. However, the analog has a longer helical extension in the N-terminal part than EX-4. The increasing helical turns may favor affinity for extracellular domain of glucagon-like peptide-1 receptor and accurate positioning of the crucial N-terminal residues in the transmembrane domains of the receptor. The analog has a stronger propensity to aggregate than the native EX-4, which is attributed to more coiled-coil interaction in the analog than in its native type. We also probed the association of EX-4 and its analog to DPC micelles and observed micelle-induced insertion of both peptides with their N- and C-termini as well as the central parts embedded in micelles and the residues near Asp9 and the residues around Trp25-Ser32 more water exposed. A single-step ligand-receptor binding model was suggested based on the analysis of these results.
影响因子：
2.9
作者：
A. Wittelsberger;M. Corich;B. Thomas;Byung-Kwon Lee;A. Barazza;P. Czodrowski;D. Mierke;M. Chorev;M. Rosenblatt
通讯作者：
A. Wittelsberger;M. Corich;B. Thomas;Byung-Kwon Lee;A. Barazza;P. Czodrowski;D. Mierke;M. Chorev;M. Rosenblatt
胰高血糖素的 9 位替换类似物使生物活性和受体结合解耦。
DOI：
--
发表时间：
1991
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Unson,CG;Macdonald,D;Ray,K;Durrah,TL;Merrifield,RB
通讯作者：
Merrifield,RB
影响因子：
2.9
作者：
Sreerama, N;Woody, RW
通讯作者：
Woody, RW