1j73
From Proteopedia
| Line 1: | Line 1: | ||
| - | [[Image:1j73.gif|left|200px]] | + | [[Image:1j73.gif|left|200px]] |
| - | + | ||
| - | '''Crystal structure of an unstable insulin analog with native activity.''' | + | {{Structure |
| + | |PDB= 1j73 |SIZE=350|CAPTION= <scene name='initialview01'>1j73</scene>, resolution 2.0Å | ||
| + | |SITE= | ||
| + | |LIGAND= <scene name='pdbligand=ZN:ZINC ION'>ZN</scene> | ||
| + | |ACTIVITY= | ||
| + | |GENE= | ||
| + | }} | ||
| + | |||
| + | '''Crystal structure of an unstable insulin analog with native activity.''' | ||
| + | |||
==Overview== | ==Overview== | ||
| Line 10: | Line 19: | ||
==About this Structure== | ==About this Structure== | ||
| - | 1J73 is a [ | + | 1J73 is a [[Protein complex]] structure of sequences from [http://en.wikipedia.org/wiki/ ]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1J73 OCA]. |
==Reference== | ==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:[http:// | + | 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:[http://www.ncbi.nlm.nih.gov/pubmed/11779231 11779231] |
[[Category: Protein complex]] | [[Category: Protein complex]] | ||
[[Category: Jia, W.]] | [[Category: Jia, W.]] | ||
| Line 24: | Line 33: | ||
[[Category: hormone-receptor interface]] | [[Category: hormone-receptor interface]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 11:59:25 2008'' |
Revision as of 09:59, 20 March 2008
| |||||||
| , resolution 2.0Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | |||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Crystal structure of an unstable insulin analog with native activity.
Contents |
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
1J73 is a Protein complex structure of sequences from [1]. 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
Page seeded by OCA on Thu Mar 20 11:59:25 2008
