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首页> 外文期刊>Biochemistry >Interactions of phenol and m-cresol in the insulin hexamer, and their effect on the association properties of B28 Pro -> Asp insulin analogues
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Interactions of phenol and m-cresol in the insulin hexamer, and their effect on the association properties of B28 Pro -> Asp insulin analogues

机译：胰岛素六聚体中苯酚和间甲酚的相互作用及其对B28 Pro-> Asp胰岛素类似物缔合性质的影响

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摘要

Insulin's natural tendency to form dimers and hexamers is significantly reduced in a mutant insulin B28 Pro --> Asp, which has been designed as a monomeric, rapid-acting hormone for therapeutic purposes. This molecule can be induced to form zinc hexamers in the presence of small phenolic derivatives which are routinely used as antimicrobial agents in insulin preparations. Two structures of B28 Asp insulin have been determined from crystals grown in the presence of phenol and Nz-cresol. in these crystals, insulin exists as R-6 zinc hexamers containing a number of phenol or nz-cresol molecules associated with aromatic side chains at the dimer-dimer inter-faces. At the monomer-monomer interfaces, the B28 Pro --> Asp mutation leads to increased conformational flexibility in the B chain C termini, resulting in the loss of important intermolecular van der Waals contacts, thus explaining the monomeric character of B28 Asp insulin. The structure of a cross-linked derivative of B28 Asp insulin, containing an Ala-Lys dipeptide linker between residues B30 Ala and Al Gly, has also determined. This forms an R-6 zinc hexamer containing several m-cresol molecules. Of particular interest in this structure are two nz-cresol molecules whose binding disrupted the beta-strand in one of the dimers. This observation suggests that the cross-link introduces mechanical strain on the B chain C terminus, thereby weakening the monomer-monomer interactions. [References: 30]
机译：在突变型胰岛素B28 Pro-> Asp中，胰岛素形成二聚体和六聚体的天然趋势显着降低，该突变体已被设计为用于治疗目的的单体，速效激素。在小酚类衍生物的存在下，该分子可被诱导形成锌六聚体，而酚类衍生物通常在胰岛素制剂中用作抗菌剂。已经从在苯酚和Nz-甲酚的存在下生长的晶体确定了B28 Asp胰岛素的两种结构。在这些晶体中，胰岛素以R-6锌六聚体的形式存在，在二聚体-二聚体界面处含有许多与芳香族侧链相关的苯酚或nz-甲酚分子。在单体-单体界面处，B28 Pro-> Asp突变导致B链C末端的构象柔韧性增加，导致重要的分子间范德华接触丧失，从而解释了B28 Asp胰岛素的单体特性。还确定了B28 Asp胰岛素的交联衍生物的结构，该衍生物在残基B30 Ala和Al Gly之间包含Ala-Lys二肽接头。这形成了包含几个间甲酚分子的R-6锌六聚体。在这种结构中特别令人感兴趣的是两个nz-甲酚分子，它们的结合破坏了一个二聚体中的β-链。该观察结果表明，交联在B链C末端引入了机械应变，从而减弱了单体-单体的相互作用。 [参考：30]

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