How insulin engages its primary binding site on the insulin receptor.
How insulin engages its primary binding site on the insulin receptor.
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作者：
胰岛素受体信号传导在哺乳动物生物学中具有中心作用，调节细胞代谢、生长、分裂、分化和存活。胰岛素抵抗有助于2型糖尿病的发病机制和阿尔茨海默病的发病;异常信号传导发生在不同的癌症中，通过与同源1型胰岛素样生长因子受体（IGF 1 R）的串扰而加剧。尽管经过了三十多年的研究，胰岛素-胰岛素受体复合物的三维结构已被证明是难以捉摸的，被产生受体蛋白的复杂性所混淆。在这里，我们提出的第一个观点，据我们所知，胰岛素与其主要结合位点的胰岛素受体的相互作用，在四个晶体结构的基础上，胰岛素结合到截断的胰岛素受体结构。胰岛素与胰岛素受体的第一个富含亮氨酸的重复结构域（L1）的直接相互作用很少，激素与胰岛素受体羧基末端α链（αCT）片段接合，该片段本身在胰岛素结合后在L1表面重塑。胰岛素和L1之间的接触仅限于胰岛素B链残基。αCT片段将B链C端β链从激素核心置换，揭示了长期提出的胰岛素受体结合后构象转换的机制。这种激素受体识别模式在受体酪氨酸激酶更广泛的家族中是新颖的。我们支持这些发现的光交联数据，把建议的相互作用的背景下的holoreceptor和等温滴定量热法数据，解剖的胰岛素受体接口。总之，我们的研究结果为胰岛素受体和IGF 1 R系统的大量生化数据提供了解释，这些数据与治疗性胰岛素类似物的设计有关。
Insulin receptor signalling has a central role in mammalian biology, regulating cellular metabolism, growth, division, differentiation and survival. Insulin resistance contributes to the pathogenesis of type 2 diabetes mellitus and the onset of Alzheimer’s disease; aberrant signalling occurs in diverse cancers, exacerbated by crosstalk with the homologous type 1 insulin-like growth factor receptor (IGF1R). Despite more than three decades of investigation, the three-dimensional structure of the insulin–insulin receptor complex has proved elusive, confounded by the complexity of producing the receptor protein. Here we present the first view, to our knowledge, of the interaction of insulin with its primary binding site on the insulin receptor, on the basis of four crystal structures of insulin bound to truncated insulin receptor constructs. The direct interaction of insulin with the first leucine-rich-repeat domain (L1) of insulin receptor is seen to be sparse, the hormone instead engaging the insulin receptor carboxy-terminal α-chain (αCT) segment, which is itself remodelled on the face of L1 upon insulin binding. Contact between insulin and L1 is restricted to insulin B-chain residues. The αCT segment displaces the B-chain C-terminal β-strand away from the hormone core, revealing the mechanism of a long-proposed conformational switch in insulin upon receptor engagement. This mode of hormone–receptor recognition is novel within the broader family of receptor tyrosine kinases. We support these findings by photo-crosslinking data that place the suggested interactions into the context of the holoreceptor and by isothermal titration calorimetry data that dissect the hormone–insulin receptor interface. Together, our findings provide an explanation for a wealth of biochemical data from the insulin receptor and IGF1R systems relevant to the design of therapeutic insulin analogues.
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影响因子：
64.8
作者：
HUA, QX;SHOELSON, SE;WEISS, MA
通讯作者：
WEISS, MA
DOI：
10.1107/s0907444996012279
发表时间：
1997-03-01
影响因子：
2.2
作者：
Kleywegt, GJ;Jones, TA
通讯作者：
Jones, TA
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
DOI：
10.1107/s0907444904016427
发表时间：
2004-12-01
影响因子：
2.2
作者：
Blanc, E;Roversi, P;Bricogne, G
通讯作者：
Bricogne, G
影响因子：
64.8
作者：
Garrett, TPJ;McKern, NM;Ward, CW
通讯作者：
Ward, CW