1t1p

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[[Image:1t1p.gif|left|200px]]
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{{STRUCTURE_1t1p| PDB=1t1p | SCENE= }}
{{STRUCTURE_1t1p| PDB=1t1p | SCENE= }}
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'''NMR STRUCTURE OF HUMAN INSULIN MUTANT HIS-B10-ASP, VAL-B12-THR, PRO-B28-LYS, LYS-B29-PRO, 15 STRUCTURES'''
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===NMR STRUCTURE OF HUMAN INSULIN MUTANT HIS-B10-ASP, VAL-B12-THR, PRO-B28-LYS, LYS-B29-PRO, 15 STRUCTURES===
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==Overview==
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Binding of insulin to the insulin receptor plays a central role in the hormonal control of metabolism. Here, we investigate possible contact sites between the receptor and the conserved non-polar surface of the B-chain. Evidence is presented that two contiguous sites in an alpha-helix, Val(B12) and Tyr(B16), contact the receptor. Chemical synthesis is exploited to obtain non-standard substitutions in an engineered monomer (DKP-insulin). Substitution of Tyr(B16) by an isosteric photo-activatable derivative (para-azido-phenylalanine) enables efficient cross-linking to the receptor. Such cross-linking is specific and maps to the L1 beta-helix of the alpha-subunit. Because substitution of Val(B12) by larger side-chains markedly impairs receptor binding, cross-linking studies at B12 were not undertaken. Structure-function relationships are instead probed by side-chains of similar or smaller volume: respective substitution of Val(B12) by alanine, threonine, and alpha-aminobutyric acid leads to activities of 1(+/-0.1)%, 13(+/-6)%, and 14(+/-5)% (relative to DKP-insulin) without disproportionate changes in negative cooperativity. NMR structures are essentially identical with native insulin. The absence of transmitted structural changes suggests that the low activities of B12 analogues reflect local perturbation of a "high-affinity" hormone-receptor contact. By contrast, because position B16 tolerates alanine substitution (relative activity 34(+/-10)%), the contribution of this neighboring interaction is smaller. Together, our results support a model in which the B-chain alpha-helix, functioning as an essential recognition element, docks against the L1 beta-helix of the insulin receptor.
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(as it appears on PubMed at http://www.pubmed.gov), where 15276842 is the PubMed ID number.
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{{ABSTRACT_PUBMED_15276842}}
==About this Structure==
==About this Structure==
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1T1P is a [[Protein complex]] structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1T1P OCA].
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1T1P is a [[Protein complex]] structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1T1P OCA].
==Reference==
==Reference==
How insulin binds: the B-chain alpha-helix contacts the L1 beta-helix of the insulin receptor., Huang K, Xu B, Hu SQ, Chu YC, Hua QX, Qu Y, Li B, Wang S, Wang RY, Nakagawa SH, Theede AM, Whittaker J, De Meyts P, Katsoyannis PG, Weiss MA, J Mol Biol. 2004 Aug 6;341(2):529-50. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/15276842 15276842]
How insulin binds: the B-chain alpha-helix contacts the L1 beta-helix of the insulin receptor., Huang K, Xu B, Hu SQ, Chu YC, Hua QX, Qu Y, Li B, Wang S, Wang RY, Nakagawa SH, Theede AM, Whittaker J, De Meyts P, Katsoyannis PG, Weiss MA, J Mol Biol. 2004 Aug 6;341(2):529-50. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/15276842 15276842]
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Mutational analysis of invariant valine B12 in insulin: implications for receptor binding., Nakagawa SH, Tager HS, Steiner DF, Biochemistry. 2000 Dec 26;39(51):15826-35. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/11123908 11123908]
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Alanine scanning mutagenesis of insulin., Kristensen C, Kjeldsen T, Wiberg FC, Schaffer L, Hach M, Havelund S, Bass J, Steiner DF, Andersen AS, J Biol Chem. 1997 May 16;272(20):12978-83. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/9148904 9148904]
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Steric requirements at position B12 for high biological activity in insulin., Hu SQ, Burke GT, Schwartz GP, Ferderigos N, Ross JB, Katsoyannis PG, Biochemistry. 1993 Mar 16;32(10):2631-5. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/8448120 8448120]
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[12-asparagine-B] human insulin. An analogue with modification in the hydrophobic core of insulin., Schwartz GP, Burke GT, Katsoyannis PG, Int J Pept Protein Res. 1981 Feb;17(2):243-55. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/7014485 7014485]
[[Category: Protein complex]]
[[Category: Protein complex]]
[[Category: Chu, Y C.]]
[[Category: Chu, Y C.]]
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[[Category: Receptor binding]]
[[Category: Receptor binding]]
[[Category: Thr-b12-dkp-insulin]]
[[Category: Thr-b12-dkp-insulin]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 09:23:52 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 29 00:30:36 2008''

Revision as of 21:30, 28 July 2008

Image:1t1p.png

Template:STRUCTURE 1t1p

NMR STRUCTURE OF HUMAN INSULIN MUTANT HIS-B10-ASP, VAL-B12-THR, PRO-B28-LYS, LYS-B29-PRO, 15 STRUCTURES

Template:ABSTRACT PUBMED 15276842

About this Structure

1T1P is a Protein complex structure. Full experimental information is available from OCA.

Reference

How insulin binds: the B-chain alpha-helix contacts the L1 beta-helix of the insulin receptor., Huang K, Xu B, Hu SQ, Chu YC, Hua QX, Qu Y, Li B, Wang S, Wang RY, Nakagawa SH, Theede AM, Whittaker J, De Meyts P, Katsoyannis PG, Weiss MA, J Mol Biol. 2004 Aug 6;341(2):529-50. PMID:15276842

Mutational analysis of invariant valine B12 in insulin: implications for receptor binding., Nakagawa SH, Tager HS, Steiner DF, Biochemistry. 2000 Dec 26;39(51):15826-35. PMID:11123908

Alanine scanning mutagenesis of insulin., Kristensen C, Kjeldsen T, Wiberg FC, Schaffer L, Hach M, Havelund S, Bass J, Steiner DF, Andersen AS, J Biol Chem. 1997 May 16;272(20):12978-83. PMID:9148904

Steric requirements at position B12 for high biological activity in insulin., Hu SQ, Burke GT, Schwartz GP, Ferderigos N, Ross JB, Katsoyannis PG, Biochemistry. 1993 Mar 16;32(10):2631-5. PMID:8448120

[12-asparagine-B] human insulin. An analogue with modification in the hydrophobic core of insulin., Schwartz GP, Burke GT, Katsoyannis PG, Int J Pept Protein Res. 1981 Feb;17(2):243-55. PMID:7014485

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