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• W2079659159 abstract "The three-dimensional structure of the insulin–insulin receptor complex has proved elusive, confounded by the complexity of producing the receptor protein; here is the first glimpse of the interaction between insulin and its primary binding site on the insulin receptor, a view based on four crystal structures of insulin bound to truncated insulin receptor complexes. Despite more than three decades of research, the three-dimensional structure of the complex between insulin and its receptor has proved elusive, confounded by the complexity of producing the receptor protein. Here is a first glimpse of the interaction between insulin and its primary binding site on the insulin receptor — a view based on four crystal structures of insulin bound to truncated receptor complexes. Surprisingly, the bulk of the interaction with the receptor leucine-rich repeat ligand-binding domain is indirect and mediated through a helical peptide segment (αCT) that is provided by the alternate insulin partner in the receptor dimer. Insulin receptor signalling has a central role in mammalian biology, regulating cellular metabolism, growth, division, differentiation and survival1,2. Insulin resistance contributes to the pathogenesis of type 2 diabetes mellitus and the onset of Alzheimer’s disease3; aberrant signalling occurs in diverse cancers, exacerbated by cross-talk with the homologous type 1 insulin-like growth factor receptor (IGF1R)4. 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 kinases5. 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." @default.
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• W2079659159 date "2013-01-01" @default.
• W2079659159 modified "2023-10-05" @default.
• W2079659159 title "How insulin engages its primary binding site on the insulin receptor" @default.
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• W2079659159 doi "https://doi.org/10.1038/nature11781" @default.
• W2079659159 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/3793637" @default.
• W2079659159 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/23302862" @default.
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