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| - | [[Image:3bxq.jpg|left|200px]] | + | {{Seed}} |
| | + | [[Image:3bxq.png|left|200px]] |
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| | {{STRUCTURE_3bxq| PDB=3bxq | SCENE= }} | | {{STRUCTURE_3bxq| PDB=3bxq | SCENE= }} |
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| - | '''The structure of a mutant insulin uncouples receptor binding from protein allostery. An electrostatic block to the TR transition'''
| + | ===The structure of a mutant insulin uncouples receptor binding from protein allostery. An electrostatic block to the TR transition=== |
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| - | ==Overview==
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| - | Single-chain insulin (SCI) analogs provide insight into the inter-relation of hormone structure, function, and dynamics. Although compatible with wild-type structure, short connecting segments (<3 residues) prevent induced fit upon receptor binding and so are essentially without biological activity. Substantial but incomplete activity can be regained with increasing linker length. Here, we describe the design, structure, and function of a single-chain insulin analog (SCI-57) containing a 6-residue linker (GGGPRR). Native receptor-binding affinity (130 +/- 8% relative to the wild type) is achieved as hindrance by the linker is offset by favorable substitutions in the insulin moiety. The thermodynamic stability of SCI-57 is markedly increased (DeltaDeltaG(u) = 0.7 +/- 0.1 kcal/mol relative to the corresponding two-chain analog and 1.9 +/- 0.1 kcal/mol relative to wild-type insulin). Analysis of inter-residue nuclear Overhauser effects demonstrates that a native-like fold is maintained in solution. Surprisingly, the glycine-rich connecting segment folds against the insulin moiety: its central Pro contacts Val(A3) at the edge of the hydrophobic core, whereas the final Arg extends the A1-A8 alpha-helix. Comparison between SCI-57 and its parent two-chain analog reveals striking enhancement of multiple native-like nuclear Overhauser effects within the tethered protein. These contacts are consistent with wild-type crystal structures but are ordinarily attenuated in NMR spectra of two-chain analogs, presumably due to conformational fluctuations. Linker-specific damping of fluctuations provides evidence for the intrinsic flexibility of an insulin monomer. In addition to their biophysical interest, ultrastable SCIs may enhance the safety and efficacy of insulin replacement therapy in the developing world.
| + | The line below this paragraph, {{ABSTRACT_PUBMED_18332129}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 18332129 is the PubMed ID number. |
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| | + | {{ABSTRACT_PUBMED_18332129}} |
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| | ==About this Structure== | | ==About this Structure== |
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| | [[Category: Receptor binding]] | | [[Category: Receptor binding]] |
| | [[Category: Tr transition]] | | [[Category: Tr transition]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu May 22 21:52:40 2008'' | + | |
| | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 07:14:21 2008'' |
Revision as of 04:14, 28 July 2008
Template:STRUCTURE 3bxq
The structure of a mutant insulin uncouples receptor binding from protein allostery. An electrostatic block to the TR transition
Template:ABSTRACT PUBMED 18332129
About this Structure
3BXQ is a Protein complex structure. Full crystallographic information is available from OCA.
Reference
Design of an Active Ultrastable Single-chain Insulin Analog: SYNTHESIS, STRUCTURE, AND THERAPEUTIC IMPLICATIONS., Hua QX, Nakagawa SH, Jia W, Huang K, Phillips NB, Hu SQ, Weiss MA, J Biol Chem. 2008 May 23;283(21):14703-16. Epub 2008 Mar 10. PMID:18332129
Page seeded by OCA on Mon Jul 28 07:14:21 2008
