1w8p

From Proteopedia

Revision as of 08:20, 3 February 2008

STRUCTURAL PROPERTIES OF THE B25TYR-NME-B26PHE INSULIN MUTANT.

Overview

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, Phe(B25) and Tyr(B26) have been swapped with the IGF-I-like Tyr(24) and, Phe(25) sequence with a simultaneous methylation of the peptide nitrogen, of residue Phe(B26). These modifications were expected to introduce a, substantial kink in the main chain, as observed at residue Phe(25) in the, IGF-I crystal structure. These alterations should provide insight into the, structural origins of insulin-IGF-I structural and functional divergence., The [Tyr(B25)NMePhe(B26)] 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 CO(A19)-NH(B25) hydrogen bond, which is, normally characteristic of T-state insulin.

Disease

Known diseases associated with this structure: Diabetes mellitus, rare form OMIM:[176730], Hyperproinsulinemia, familial OMIM:[176730], MODY, one form OMIM:[176730]

About this Structure

1W8P is a Protein complex structure of sequences from Homo sapiens with and as ligands. Known structural/functional Site: . Full crystallographic information is available from OCA.

Reference

Toward the insulin-IGF-I intermediate structures: functional and structural properties of the [TyrB25NMePheB26] insulin mutant., Zakova L, Brynda J, Au-Alvarez O, Dodson EJ, Dodson GG, Whittingham JL, Brzozowski AM, Biochemistry. 2004 Dec 28;43(51):16293-300. PMID:15610023

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