1jca
From Proteopedia
| Line 1: | Line 1: | ||
[[Image:1jca.gif|left|200px]] | [[Image:1jca.gif|left|200px]] | ||
| - | + | <!-- | |
| - | + | The line below this paragraph, containing "STRUCTURE_1jca", creates the "Structure Box" on the page. | |
| - | + | You may change the PDB parameter (which sets the PDB file loaded into the applet) | |
| - | + | or the SCENE parameter (which sets the initial scene displayed when the page is loaded), | |
| - | | | + | or leave the SCENE parameter empty for the default display. |
| - | | | + | --> |
| - | + | {{STRUCTURE_1jca| PDB=1jca | SCENE= }} | |
| - | + | ||
| - | + | ||
| - | }} | + | |
'''Non-standard Design of Unstable Insulin Analogues with Enhanced Activity''' | '''Non-standard Design of Unstable Insulin Analogues with Enhanced Activity''' | ||
| Line 19: | Line 16: | ||
==About this Structure== | ==About this Structure== | ||
| - | 1JCA is a [[Protein complex]] structure | + | 1JCA is a [[Protein complex]] structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1JCA OCA]. |
==Reference== | ==Reference== | ||
| Line 33: | Line 30: | ||
[[Category: Weiss, M A.]] | [[Category: Weiss, M A.]] | ||
[[Category: Zhao, M.]] | [[Category: Zhao, M.]] | ||
| - | [[Category: | + | [[Category: A8-lysine human insulin]] |
| - | [[Category: | + | [[Category: Insulin receptor]] |
| - | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 21:02:54 2008'' | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | |
Revision as of 18:02, 2 May 2008
Non-standard Design of Unstable Insulin Analogues with Enhanced Activity
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.
About this Structure
1JCA 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 Page seeded by OCA on Fri May 2 21:02:54 2008
