1kmf

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NMR STRUCTURE OF HUMAN INSULIN MUTANT ILE-A2-ALLO-ILE, HIS-B10-ASP, PRO-B28-LYS, LYS-B29-PRO, 15 STRUCTURES

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

The hydrophobic core of vertebrate insulins contains an invariant isoleucine residue at position A2. Lack of variation may reflect this side-chain's dual contribution to structure and function: Ile(A2) is proposed both to stabilize the A1-A8 alpha-helix and to contribute to a "hidden" functional surface exposed on receptor binding. Substitution of Ile(A2) by alanine results in segmental unfolding of the A1-A8 alpha-helix, lower thermodynamic stability and impaired receptor binding. Such a spectrum of perturbations, although of biophysical interest, confounds interpretation of structure-activity relationships. To investigate the specific contribution of Ile(A2) to insulin's functional surface, we have employed non-standard mutagenesis: inversion of side-chain chirality in engineered monomer allo-Ile(A2)-DKP-insulin. Although the analogue retains native structure and stability, its affinity for the insulin receptor is impaired by 50-fold. Thus, whereas insulin's core readily accommodates allo-isoleucine at A2, its activity is exquisitely sensitive to chiral inversion. We propose that the Ile(A2) side-chain inserts within a chiral pocket of the receptor as part of insulin's hidden functional surface.

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

1KMF is a Protein complex structure of sequences from [1]. Full crystallographic information is available from OCA.

Reference

Chiral mutagenesis of insulin's hidden receptor-binding surface: structure of an allo-isoleucine(A2) analogue., Xu B, Hua QX, Nakagawa SH, Jia W, Chu YC, Katsoyannis PG, Weiss MA, J Mol Biol. 2002 Feb 22;316(3):435-41. PMID:11866509

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