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(New page: 200px<br /> <applet load="1kmf" size="450" color="white" frame="true" align="right" spinBox="true" caption="1kmf" /> '''NMR STRUCTURE OF HUMAN INSULIN MUTANT ILE-A...) |
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'''NMR STRUCTURE OF HUMAN INSULIN MUTANT ILE-A2-ALLO-ILE, HIS-B10-ASP, PRO-B28-LYS, LYS-B29-PRO, 15 STRUCTURES'''<br /> | '''NMR STRUCTURE OF HUMAN INSULIN MUTANT ILE-A2-ALLO-ILE, HIS-B10-ASP, PRO-B28-LYS, LYS-B29-PRO, 15 STRUCTURES'''<br /> | ||
==Overview== | ==Overview== | ||
| - | The hydrophobic core of vertebrate insulins contains an invariant | + | The hydrophobic core of vertebrate insulins contains an invariant isoleucine residue at position A2. Lack of variation may reflect this side-chain's dual contribution to structure and function: Ile(A2) is proposed both to stabilize the A1-A8 alpha-helix and to contribute to a "hidden" functional surface exposed on receptor binding. Substitution of Ile(A2) by alanine results in segmental unfolding of the A1-A8 alpha-helix, lower thermodynamic stability and impaired receptor binding. Such a spectrum of perturbations, although of biophysical interest, confounds interpretation of structure-activity relationships. To investigate the specific contribution of Ile(A2) to insulin's functional surface, we have employed non-standard mutagenesis: inversion of side-chain chirality in engineered monomer allo-Ile(A2)-DKP-insulin. Although the analogue retains native structure and stability, its affinity for the insulin receptor is impaired by 50-fold. Thus, whereas insulin's core readily accommodates allo-isoleucine at A2, its activity is exquisitely sensitive to chiral inversion. We propose that the Ile(A2) side-chain inserts within a chiral pocket of the receptor as part of insulin's hidden functional surface. |
==Disease== | ==Disease== | ||
| Line 11: | Line 10: | ||
==About this Structure== | ==About this Structure== | ||
| - | 1KMF is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/ ]. Full crystallographic information is available from [http:// | + | 1KMF is a [http://en.wikipedia.org/wiki/Protein_complex 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=1KMF OCA]. |
==Reference== | ==Reference== | ||
Chiral mutagenesis of insulin's hidden receptor-binding surface: structure of an allo-isoleucine(A2) analogue., Xu B, Hua QX, Nakagawa SH, Jia W, Chu YC, Katsoyannis PG, Weiss MA, J Mol Biol. 2002 Feb 22;316(3):435-41. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=11866509 11866509] | Chiral mutagenesis of insulin's hidden receptor-binding surface: structure of an allo-isoleucine(A2) analogue., Xu B, Hua QX, Nakagawa SH, Jia W, Chu YC, Katsoyannis PG, Weiss MA, J Mol Biol. 2002 Feb 22;316(3):435-41. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=11866509 11866509] | ||
[[Category: Protein complex]] | [[Category: Protein complex]] | ||
| - | [[Category: Chu, Y | + | [[Category: Chu, Y C.]] |
| - | [[Category: Hua, Q | + | [[Category: Hua, Q X.]] |
[[Category: Jia, W.]] | [[Category: Jia, W.]] | ||
| - | [[Category: Katsoyannis, P | + | [[Category: Katsoyannis, P G.]] |
| - | [[Category: Nakagawa, S | + | [[Category: Nakagawa, S H.]] |
| - | [[Category: Weiss, M | + | [[Category: Weiss, M A.]] |
[[Category: Xu, B.]] | [[Category: Xu, B.]] | ||
[[Category: hormone]] | [[Category: hormone]] | ||
| Line 27: | Line 26: | ||
[[Category: mutant]] | [[Category: mutant]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 13:35:41 2008'' |
Revision as of 11:35, 21 February 2008
|
NMR STRUCTURE OF HUMAN INSULIN MUTANT ILE-A2-ALLO-ILE, HIS-B10-ASP, PRO-B28-LYS, LYS-B29-PRO, 15 STRUCTURES
Contents |
Overview
The hydrophobic core of vertebrate insulins contains an invariant isoleucine residue at position A2. Lack of variation may reflect this side-chain's dual contribution to structure and function: Ile(A2) is proposed both to stabilize the A1-A8 alpha-helix and to contribute to a "hidden" functional surface exposed on receptor binding. Substitution of Ile(A2) by alanine results in segmental unfolding of the A1-A8 alpha-helix, lower thermodynamic stability and impaired receptor binding. Such a spectrum of perturbations, although of biophysical interest, confounds interpretation of structure-activity relationships. To investigate the specific contribution of Ile(A2) to insulin's functional surface, we have employed non-standard mutagenesis: inversion of side-chain chirality in engineered monomer allo-Ile(A2)-DKP-insulin. Although the analogue retains native structure and stability, its affinity for the insulin receptor is impaired by 50-fold. Thus, whereas insulin's core readily accommodates allo-isoleucine at A2, its activity is exquisitely sensitive to chiral inversion. We propose that the Ile(A2) side-chain inserts within a chiral pocket of the receptor as part of insulin's hidden functional surface.
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
1KMF is a Protein complex structure of sequences from [1]. Full crystallographic information is available from OCA.
Reference
Chiral mutagenesis of insulin's hidden receptor-binding surface: structure of an allo-isoleucine(A2) analogue., Xu B, Hua QX, Nakagawa SH, Jia W, Chu YC, Katsoyannis PG, Weiss MA, J Mol Biol. 2002 Feb 22;316(3):435-41. PMID:11866509
Page seeded by OCA on Thu Feb 21 13:35:41 2008
Categories: Protein complex | Chu, Y C. | Hua, Q X. | Jia, W. | Katsoyannis, P G. | Nakagawa, S H. | Weiss, M A. | Xu, B. | Hormone | Human insulin | Mutant
