Shooter G K, Magee B, Soos M A, Francis G L, Siddle K, Wallace J C
Department of Biochemistry, University of Adelaide, South Australia, Australia.
J Mol Endocrinol. 1996 Dec;17(3):237-46. doi: 10.1677/jme.0.0170237.
Insulin-like growth factor-I (IGF-I) analogues were produced with the aim of identifying IGF-I residues that contribute to the specificity of binding to the type 1 IGF receptor as opposed to the insulin receptor. Receptor binding properties of a series of A- and B-domain analogues were compared using rat L6 myoblasts, soluble human IGF type 1 receptors and soluble human insulin receptor isoforms HIR-A (-Ex11) and HIR-B (+Ex11). IGF-I analogues, [Leu8] IGF-I and [Phe59] IGF-I, were shown to exhibit respectively, a 28- and 17-fold decrease in affinity for the HIR-A with only a 6- and 5-fold decrease in affinity for the human IGF type 1 receptor. In contrast, the analogue [His4] IGF-I was equipotent to IGF-I in binding to the soluble type 1 IGF receptor while showing 7-fold and 4-fold increases in HIR-A and HIR-B binding respectively. Furthermore, [Leu62] IGF-I was 8-fold less potent than IGF-I in soluble IGF type 1 receptor binding but only showed a 2-fold decrease in HIR-A and HIR-B binding. Our study supports the conclusion that the co-evolution of the IGF-I and insulin receptor/ligand systems has resulted in subtle structural differences in the A- and B-regions of each ligand important for defining receptor binding specificity.
胰岛素样生长因子-I（IGF-I）类似物的产生旨在确定IGF-I中与1型IGF受体而非胰岛素受体结合特异性相关的残基。使用大鼠L6成肌细胞、可溶性人IGF-1受体以及可溶性人胰岛素受体亚型HIR-A（-Ex11）和HIR-B（+Ex11）比较了一系列A域和B域类似物的受体结合特性。IGF-I类似物[Leu8]IGF-I和[Phe59]IGF-I对HIR-A的亲和力分别降低了28倍和17倍，而对人IGF-1受体的亲和力仅分别降低了6倍和5倍。相比之下，类似物[His4]IGF-I与可溶性1型IGF受体结合时与IGF-I效力相当，而与HIR-A和HIR-B的结合分别增加了7倍和4倍。此外，[Leu62]IGF-I在可溶性IGF-1受体结合方面比IGF-I效力低8倍，但在HIR-A和HIR-B结合方面仅降低了2倍。我们的研究支持这样的结论，即IGF-I和胰岛素受体/配体系统的共同进化导致了每个配体A区和B区在结构上存在细微差异，这些差异对于确定受体结合特异性很重要。
