A versatile insulin analog with high potency for both insulin and insulin-like growth factor 1 receptors: Structural implications for receptor binding.
A versatile insulin analog with high potency for both insulin and insulin-like growth factor 1 receptors: Structural implications for receptor binding.
复制标题
DOI：
10.1074/jbc.ra118.004852
复制
发表时间：
2018-10-26
期刊：
影响因子：
--
通讯作者：
Selicharová I
中科院分区：
文献类型：
--
作者：
Chrudinová M;Žáková L;Marek A;Socha O;Buděšínský M;Hubálek M;Pícha J;Macháčková K;Jiráček J;Selicharová I
胰岛素和胰岛素样生长因子1（IGF-1）是参与代谢和生长调节的密切相关的激素。它们通过激活酪氨酸激酶型受体（胰岛素受体（IR-A和IR-B）和IGF-1受体（IGF-1 R））发挥功能。尽管一级和三维结构相似，胰岛素和IGF-1结合非同源受体的亲和力大大降低。我们制备了[d-HisB 24，GlyB 31，TyrB 32]-胰岛素，其以高亲和力结合所有三种受体（相对于胰岛素，其与IR-A的结合亲和力分别为251或338%，与IGF-1 R的结合亲和力相对于IGF-1为12.4%）。我们制备了其他修饰的胰岛素，目的是解释[d-HisB 24，GlyB 31，TyrB 32]-胰岛素的多功能性。通过对这些胰岛素类似物的结构、活性和动力学研究，我们得出结论，[d-HisB 24、GlyB 31、TyrB 32]-胰岛素刺激所有三种受体的能力是由B24处的反向手性结合B链C末端两个额外残基的延伸引起的结构变化提供的。我们假设结构变化允许引导B链C末端与受体进行一些额外的相互作用。这些不寻常的相互作用导致IR的解离速率降低，相反，使其更容易与IGF-1 R结合。所有的结构变化都发生在激素的位点1，这被认为是与受体的位点1相互作用。该研究的结果表明，仅仅修饰激素的位点1就足以改变胰岛素的受体特异性。
Insulin and insulin-like growth factor 1 (IGF-1) are closely related hormones involved in the regulation of metabolism and growth. They elicit their functions through activation of tyrosine kinase–type receptors: insulin receptors (IR-A and IR-B) and IGF-1 receptor (IGF-1R). Despite similarity in primary and three-dimensional structures, insulin and IGF-1 bind the noncognate receptor with substantially reduced affinity. We prepared [d-HisB24, GlyB31, TyrB32]-insulin, which binds all three receptors with high affinity (251 or 338% binding affinity to IR-A respectively to IR-B relative to insulin and 12.4% binding affinity to IGF-1R relative to IGF-1). We prepared other modified insulins with the aim of explaining the versatility of [d-HisB24, GlyB31, TyrB32]-insulin. Through structural, activity, and kinetic studies of these insulin analogs, we concluded that the ability of [d-HisB24, GlyB31, TyrB32]-insulin to stimulate all three receptors is provided by structural changes caused by a reversed chirality at the B24 combined with the extension of the C terminus of the B chain by two extra residues. We assume that the structural changes allow the directing of the B chain C terminus to some extra interactions with the receptors. These unusual interactions lead to a decrease of dissociation rate from the IR and conversely enable easier association with IGF-1R. All of the structural changes were made at the hormones' Site 1, which is thought to interact with the Site 1 of the receptors. The results of the study suggest that merely modifications of Site 1 of the hormone are sufficient to change the receptor specificity of insulin.
影响因子：
2.9
作者：
Sajid W;Holst PA;Kiselyov VV;Andersen AS;Conlon JM;Kristensen C;Kjeldsen T;Whittaker J;Chan SJ;De Meyts P
通讯作者：
De Meyts P