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Toward the insulin-IGF-I intermediate structures: functional and structural properties of the [TyrB25NMePheB26] insulin mutant

Žáková, L., Brynda, J., Au-Alvarez, O., Dodson, E.J., Dodson, G.G., Whittingham, J.L. and Brzozowski, A.M. (2004) Toward the insulin-IGF-I intermediate structures: functional and structural properties of the [TyrB25NMePheB26] insulin mutant. Biochemistry, 43 (51). 16293 - 16300. ISSN 0006-2960

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Abstract

The origins of differentiation of insulin from insulin-like growth factor I (IGF-I) are still unknown. To address the problem of a structural and biological switch from the mostly metabolic hormonal activity of insulin to the predominant growth factor activities of IGF-I, an insulin analogue with IGF-I-like structural features has been synthesized. Insulin residues PheB25 and TyrB26 have been swapped with the IGF-I-like Tyr24 and Phe25 sequence with a simultaneous methylation of the peptide nitrogen of residue PheB26. These modifications were expected to introduce a substantial kink in the main chain, as observed at residue Phe25 in the IGF-I crystal structure. These alterations should provide insight into the structural origins of insulin−IGF-I structural and functional divergence. The [TyrB25NMePheB26] mutant has been characterized, and its crystal structure has been determined. Surprisingly, all of these changes are well accommodated within an insulin R6 hexamer. Only one molecule of each dimer in the hexamer responds to the structural alterations, the other remaining very similar to wild-type insulin. All alterations, modest in their scale, cumulate in the C-terminal part of the B-chain (residues B23−B30), which moves toward the core of the insulin molecule and is associated with a significant shift of the A1 helix toward the C-terminus of the B-chain. These changes do not produce the expected bend of the main chain, but the fold of the mutant does reflect some structural characteristics of IGF-1, and in addition establishes the COA19−NHB25 hydrogen bond, which is normally characteristic of T-state insulin.

Item Type: Article
Institution: The University of York
Academic Units: The University of York > Chemistry (York)
Depositing User: York RAE Import
Date Deposited: 14 Aug 2009 10:34
Last Modified: 14 Aug 2009 10:34
Published Version: http://dx.doi.org/10.1021/bi048856u
Status: Published
Publisher: ACS American Chemical Society
Identification Number: 10.1021/bi048856u
URI: http://eprints.whiterose.ac.uk/id/eprint/5661

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