ArticleProceedings of the National Academy of Sciences of the United States of America2012
α-Helical element at the hormone-binding surface of the insulin receptor functions as a signaling element to activate its tyrosine kinase.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 35 citations in OpenAlex.
- Noncanonical Amino Acid Tools and Their Application to Membrane Protein Studies.Chemical reviews · 2024Review
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- Capturing Peptide-GPCR Interactions and Their Dynamics.Molecules (Basel, Switzerland) · 2020Review
- Effects of Vaspin on Insulin Resistance in Rats and Underlying Mechanisms.Scientific reports · 2018Article
- Computational study of the activity, dynamics, energetics and conformations of insulin analogues using molecular dynamics simulations: Application to hyperinsulinemia and the critical residue B26.Biochemistry and biophysics reports · 2017Article
- Theoretical and computational studies of peptides and receptors of the insulin family.Membranes · 2015Review
- Molecular Dynamics Simulations of Insulin: Elucidating the Conformational Changes that Enable Its Binding.PloS one · 2015Article
- Remembering donald f. Steiner.Frontiers in endocrinology · 2015Review
- Article
- Human insulin analogues modified at the B26 site reveal a hormone conformation that is undetected in the receptor complex.Acta crystallographica. Section D, Biological crystallography · 2014Article
- Protective hinge in insulin opens to enable its receptor engagement.Proceedings of the National Academy of Sciences of the United States of America · 2014Article
- Article
- Design of non-standard insulin analogs for the treatment of diabetes mellitus.Current diabetes reports · 2012Review
- Identification of key residues essential for the structural fold and receptor selectivity within the A-chain of human gene-2 (H2) relaxin.The Journal of biological chemistry · 2012Article
- Agonism and antagonism at the insulin receptor.PloS one · 2012Article
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
Abstract
The primary hormone-binding surface of the insulin receptor spans one face of the N-terminal β-helix of the α-subunit (the L1 domain) and an α-helix in its C-terminal segment (αCT). Crystallographic analysis of the free ectodomain has defined a contiguous dimer-related motif in which the αCT α-helix packs against L1 β-strands 2 and 3. To relate structure to function, we exploited expanded genetic-code technology to insert photo-activatable probes at key sites in L1 and αCT. The pattern of αCT-mediated photo-cross-linking within the free and bound receptor is in accord with the crystal structure and prior mutagenesis. Surprisingly, L1 photo-probes in β-strands 2 and 3, predicted to be shielded by αCT, efficiently cross-link to insulin. Furthermore, anomalous mutations were identified on neighboring surfaces of αCT and insulin that impair hormone-dependent activation of the intracellular receptor tyrosine kinase (contained within the transmembrane β-subunit) disproportionately to their effects on insulin binding. Taken together, these results suggest that αCT, in addition to its hormone-recognition role, provides a signaling element in the mechanism of receptor activation.
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Registered trials
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