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A structural switch in a mutant insulin exposes key residues for receptor binding
S Ludvigsen1, H B Olsen, N C Kaarsholm
1Novo Nordisk A/S, Bagsvaerd, Denmark.
Journal of Molecular Biology
|June 24, 1998
Summary
Insulin receptor binding involves a subtle structural shift in the insulin B-chain's C-terminus. This rearrangement, observed in a mutant insulin, explains receptor binding properties and likely occurs in native insulin during binding.
Area of Science:
- Biochemistry
- Structural Biology
- Molecular Endocrinology
Background:
- The precise structural changes in insulin upon receptor binding remain unclear.
- Conformational changes in the insulin B-chain's carboxy-terminal are widely suspected.
- Specific mutations at PheB24, like glycine, are surprisingly tolerated, suggesting unique structural roles.
Purpose of the Study:
- To elucidate the structural basis of insulin receptor binding.
- To investigate the conformational changes in the insulin B-chain's C-terminus.
- To correlate structural rearrangements with receptor binding properties.
Main Methods:
- Solution structure determination of a biologically active insulin mutant ((GluB16, GlyB24, desB30)-insulin).
- Analysis of the C-terminal decapeptide rearrangement at pH 8.
- Comparison of mutant structure with native insulin.
Main Results:
- A subtle but well-defined rearrangement of the C-terminal decapeptide was observed.
- The B20-23 turn perturbation allows PheB25 to occupy the PheB24 position.
- The exposed protein surface explains the binding of various insulin analogs.
Conclusions:
- The observed structural switch is likely driven by the invariant core residues of insulin.
- An analogous C-terminal rearrangement probably occurs in native insulin upon receptor binding.
- This structural plasticity is key to understanding insulin's biological activity.