RECEPTOR-BINDING REDEFINED BY A STRUCTURAL SWITCH IN A MUTANT HUMAN INSULIN
RECEPTOR-BINDING REDEFINED BY A STRUCTURAL SWITCH IN A MUTANT HUMAN INSULIN
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DOI：
10.1038/354238a0
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发表时间：
1991-11-21
期刊：
影响因子：
64.8
通讯作者：
WEISS, MA
中科院分区：
文献类型：
--
作者：
HUA, QX;SHOELSON, SE;WEISS, MA
胰岛素的晶体结构已被确定为各种不同的形式1-5，其与受体识别的相关性长期以来一直是推测的主题2，6，7。最近，已经确定了无活性胰岛素类似物的晶体结构，并且令人惊讶地发现其具有与天然胰岛素相同的构象8，9。在此基础上，Dodson及其同事提出，已知的胰岛素晶体结构反映了非活性构象，并且活性特异性地需要构象的变化，提出B链的羧基末端残基与A链的氨基末端残基分离8。在这里，我们报告的解决方案结构的活性胰岛素突变体7，10，确定二维NMR，这支持了这一假设。在突变体中，B链的羧基末端β-转角和β-链不稳定，并且不包裹分子的其余部分。我们认为，类似的分离的羧基末端区域的B-链发生在天然胰岛素结合其受体。我们发现B链的部分解折叠暴露了另一种蛋白质表面，这使一系列异常胰岛素类似物的受体结合特性合理化7，11 -13，包括与男性糖尿病相关的突变胰岛素14，15。
CRYSTAL Structures of insulin have been determined in various distinct forms 1-5, the relevance of which to receptor recognition has long been the subject of speculation 2,6,7. Recently the crystal structure of an inactive insulin analogue has been determined and, surprisingly, found to have a conformation identical to native insulin 8,9. On this basis Dodson and colleagues have suggested that the known insulin crystal structures reflect an inactive conformation, and that a change in conformation is required for activity-specifically, the carboxy terminal residues of the B-chain are proposed to separate from the amino terminal residues of the A-chain 8. Here we report the solution structure of an active insulin mutant 7,10, determined by two-dimensional NMR, which supports this hypothesis. In the mutant, the carboxy terminal beta-turn and beta-strand of the B-chain are destabilized and do not pack across the rest of the molecule. We suggest that analogous detachment of the carboxy terminal region of the B-chain occurs in native insulin on binding to its receptor. Our finding that partial unfolding of the B-chain exposes an alternative protein surface rationalizes the receptor-binding properties of a series of anomalous insulin analogues 7,11-13, including a mutant insulin associated with diabetes mellitus in man 14,15.