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1j73

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{{STRUCTURE_1j73| PDB=1j73 | SCENE= }}
{{STRUCTURE_1j73| PDB=1j73 | SCENE= }}
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'''Crystal structure of an unstable insulin analog with native activity.'''
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===Crystal structure of an unstable insulin analog with native activity.===
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==Overview==
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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.
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The line below this paragraph, {{ABSTRACT_PUBMED_11779231}}, adds the Publication Abstract to the page
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(as it appears on PubMed at http://www.pubmed.gov), where 11779231 is the PubMed ID number.
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{{ABSTRACT_PUBMED_11779231}}
==About this Structure==
==About this Structure==
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[[Category: A8-diaminobutyric acid human insulin]]
[[Category: A8-diaminobutyric acid human insulin]]
[[Category: Hormone-receptor interface]]
[[Category: Hormone-receptor interface]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 20:51:49 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 1 14:34:12 2008''

Revision as of 11:34, 1 July 2008

Image:1j73.png

Template:STRUCTURE 1j73

Crystal structure of an unstable insulin analog with native activity.

Template:ABSTRACT PUBMED 11779231

About this Structure

1J73 is a Protein complex structure. 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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