Importance of the character and configuration of residues B24, B25, and B26 in insulin-receptor interactions.
Importance of the character and configuration of residues B24, B25, and B26 in insulin-receptor interactions.
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DOI：
10.1016/s0021-9258(18)52312-7
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发表时间：
1991-01
期刊：
影响因子：
--
通讯作者：
R. Mirmira;S. Nakagawa;H. Tager
中科院分区：
文献类型：
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作者：
R. Mirmira;S. Nakagawa;H. Tager
利用分离的犬肝细胞和胰酶催化半合成的胰岛素类似物，我们研究了胰岛素COOH末端B链区的芳香族三联体PheB24-PheB25-TyrB26在指导胰岛素-受体相互作用亲和力中的重要性。对该区域内带有转位或替换的类似物(通过Tyr、D-Tyr或其相应的3，5-二碘衍生物)的受体结合能力的分析表明，在接受构型变化([D-TyrB24，PheB26]胰岛素和[D-TyrB25，PheB26]胰岛素分别表现出160%和0.1%的胰岛素受体结合能力)和详细的侧链结构([TyrB24，PheB26]胰岛素和[TyrB25，PheB26]胰岛素分别表现出2%和80%的胰岛素受体结合能力)方面，两者在接受结构变化方面存在很大的差异。另外的实验用分析放射性碘化的方法研究了胰岛素及其类似物在选定的多肽浓度下的4个酪氨酸残基的溶剂可及性。虽然发现两个类似物([TyrB25，PheB26]胰岛素和[D-TyrB24，PheB26]胰岛素)发生自我聚集，但没有发现类似物的聚集能力与其与胰岛素受体相互作用的效力之间存在严格的相关性。从胰岛素B链COOH-末端结构域的侧链和主链结构之间的相互作用以及决定胰岛素-受体相互作用亲和力的胰岛素的结构属性方面讨论了相关发现。
By use of isolated canine hepatocytes and insulin analogs prepared by trypsin-catalyzed semisynthesis, we have investigated the importance of the aromatic triplet PheB24-PheB25-TyrB26 of the COOH-terminal B-chain domain of insulin in directing the affinity of insulin-receptor interactions. Analysis of the receptor binding potencies of analogs bearing transpositions or replacements (by Tyr, D-Tyr or their corresponding 3,5-diiodo derivatives) in this region demonstrates a wide divergence in the acceptance both of configurational change (with [D-TyrB24,PheB26]insulin and [D-TyrB25,PheB26]insulin exhibiting 160 and 0.1% of the receptor binding potency of insulin, respectively) and of detailed side chain structure (with [TyrB24,PheB26]insulin and [TyrB25,PheB26]insulin exhibiting 2 and 80% of the receptor binding potency of insulin, respectively). Additional experiments addressed the solvent accessibilities of the 4 tyrosine residues of insulin and the insulin analogs at selected peptide concentrations by use of analytical radioiodination. Whereas two analogs ([TyrB25,PheB26]insulin and [D-TyrB24,PheB26]insulin) were found to undergo self aggregation, no strict correlation was found between the ability of an analog to aggregate and its potency for interaction with the insulin receptor. Related findings are discussed in terms of the interplay between side chain and main chain structure in the COOH-terminal domain of the insulin B-chain and the structural attributes of insulin that determine the affinity of insulin-receptor interactions.