1jca

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spinqualitylabelsall models 1jca, resolution 2.5Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Non-standard Design of Unstable Insulin Analogues with Enhanced Activity

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

The design of insulin analogues has emphasized stabilization or, destabilization of structural elements according to established principles, of protein folding. To this end, solvent-exposed side-chains extrinsic to, the receptor-binding surface provide convenient sites of modification. An, example is provided by an unfavorable helical C-cap (Thr(A8)) whose, substitution by favorable amino acids (His(A8) or Arg(A8)) has yielded, analogues of improved stability. Remarkably, these analogues also exhibit, enhanced activity, suggesting that activity may correlate with stability., Here, we test this hypothesis by substitution of diaminobutyric acid, (Dab(A8)), like threonine an amino acid of low helical propensity. The, crystal structure of Dab(A8)-insulin is similar to those of native insulin, and the related analogue Lys(A8)-insulin. Although no more stable than, native insulin, the non-standard analogue is twice as active. Stability, and affinity can therefore be uncoupled. To investigate alternative, mechanisms by which A8 substitutions enhance activity, multiple, substitutions were introduced. Surprisingly, diverse aliphatic, aromatic, and polar side-chains enhance receptor binding and biological activity., Because no relationship is observed between activity and helical, propensity, we propose that local interactions between the A8 side-chain, and an edge of the hormone-receptor interface modulate affinity., Dab(A8)-insulin illustrates the utility of non-standard amino acids in, hypothesis-driven protein design.

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

1JCA is a Protein complex structure of sequences from [1] with ZN as ligand. Full crystallographic information is available from OCA.

Reference

Non-standard insulin design: structure-activity relationships at the periphery of the insulin receptor., Weiss MA, Wan Z, Zhao M, Chu YC, Nakagawa SH, Burke GT, Jia W, Hellmich R, Katsoyannis PG, J Mol Biol. 2002 Jan 11;315(2):103-11. PMID:11779231

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