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Related Experiment Videos

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

Q X Hua1, S E Shoelson, M Kochoyan

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

Nature
|November 21, 1991
PubMed
Summary
This summary is machine-generated.

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Insulin

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Structural Biology

Background:

  • Insulin's crystal structures have been studied, but their relevance to receptor binding remains speculative.
  • Previous studies suggested insulin requires a conformational change for activity, involving B-chain residues.
  • An inactive insulin analogue's crystal structure revealed a conformation identical to native insulin.

Purpose of the Study:

  • To investigate the conformational changes of insulin related to receptor binding.
  • To test the hypothesis that B-chain carboxy-terminal residues detach for insulin activity.
  • To elucidate the structural basis for insulin receptor recognition.

Main Methods:

  • Determined the solution structure of an active insulin mutant using two-dimensional Nuclear Magnetic Resonance (2D NMR).

Related Experiment Videos

  • Analyzed the conformational dynamics of the B-chain in the active insulin mutant.
  • Correlated structural findings with receptor-binding properties of insulin analogues.

    • Main Results:

    • The active insulin mutant's structure showed destabilized B-chain carboxy-terminal beta-turn and beta-strand.
    • These regions did not pack against the rest of the molecule in the active mutant.
    • Partial unfolding of the B-chain exposed an alternative protein surface.

    Conclusions:

    • The study supports the hypothesis that B-chain carboxy-terminal residues detach for insulin activity.
    • This conformational change likely occurs in native insulin upon receptor binding.
    • The findings explain the receptor-binding properties of various insulin analogues, including a mutant linked to diabetes mellitus.