1lkq

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NMR STRUCTURE OF HUMAN INSULIN MUTANT ILE-A2-GLY, VAL-A3-GLY, HIS-B10-ASP, PRO-B28-LYS, LYS-B29-PRO, 20 STRUCTURES

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

The A and B chains of insulin combine to form native disulfide bridges, without detectable isomers. The fidelity of chain combination thus, recapitulates the folding of proinsulin, a precursor protein in which the, two chains are tethered by a disordered connecting peptide. We have, recently shown that chain combination is blocked by seemingly conservative, substitutions in the C-terminal alpha-helix of the A chain. Such analogs, once formed, nevertheless retain high biological activity. By contrast, we, demonstrate here that chain combination is robust to non-conservative, substitutions in the N-terminal alpha-helix. Introduction of multiple, glycine substitutions into the N-terminal segment of the A chain (residues, A1-A5) yields analogs that are less stable than native insulin and, essentially without biological activity. (1)H NMR studies of a, representative analog lacking invariant side chains Ile(A2) and Val(A3) (A, chain sequence GGGEQCCTSICSLYQLENYCN; substitutions are italicized and, cysteines are underlined) demonstrate local unfolding of the A1-A5 segment, in an otherwise native-like structure. That this and related partial folds, retain efficient disulfide pairing suggests that the native N-terminal, alpha-helix does not participate in the transition state of the reaction., Implications for the hierarchical folding mechanisms of proinsulin and, insulin-like growth factors are discussed.

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

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

Reference

Mechanism of insulin chain combination. Asymmetric roles of A-chain alpha-helices in disulfide pairing., Hua QX, Chu YC, Jia W, Phillips NF, Wang RY, Katsoyannis PG, Weiss MA, J Biol Chem. 2002 Nov 8;277(45):43443-53. Epub 2002 Aug 23. PMID:12196530

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