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Receptor binding redefined by a structural switch in a mutant human insulin

Nature volume 354, pages 238241 (21 November 1991) | Download Citation

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Abstract

CRYSTAL structures of insulin have been determined in various distinct forms1–5, the relevance of which to receptor recognition has long been the subject of speculation2,6,7. Recently the crystal structure of an inactive insulin analogue has been determined and, surprisingly, found to have a conformation identical to native insulin8,9. 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-chain8. Here we report the solution structure of an active insulin mutant7,10, determined by two-dimensional NMR, which supports this hypothesis. In the mutant, the carboxy terminal β-turn and β-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 analogues7,11–13, including a mutant insulin associated with diabetes mellitus in man14,15.

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Affiliations

  1. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Qing Xin Hua
    • , Michel Kochoyan
    •  & Michael A. Weiss
  2. Joslin Diabetes Center and Departments of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02215, USA

    • Steven E. Shoelson
  3. Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA

    • Michael A. Weiss
  4. Permanent addresses: Institute of Biophysics, Academia Sinica, Beijing, China (Q.X.H.); CNRS URA 32, Biop. Polytechnique, 91128 Palaiseau, France (M.K.).

    • Qing Xin Hua
    •  & Michel Kochoyan

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https://doi.org/10.1038/354238a0

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