1t1q
From Proteopedia
(New page: 200px<br /> <applet load="1t1q" size="450" color="white" frame="true" align="right" spinBox="true" caption="1t1q" /> '''NMR STRUCTURE OF HUMAN INSULIN MUTANT HIS-B...) |
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'''NMR STRUCTURE OF HUMAN INSULIN MUTANT HIS-B10-ASP, VAL-B12-ABA, PRO-B28-LYS, LYS-B29-PRO, 15 STRUCTURES'''<br /> | '''NMR STRUCTURE OF HUMAN INSULIN MUTANT HIS-B10-ASP, VAL-B12-ABA, PRO-B28-LYS, LYS-B29-PRO, 15 STRUCTURES'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Binding of insulin to the insulin receptor plays a central role in the | + | 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. |
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 1T1Q 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:// | + | 1T1Q 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=1T1Q 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://ispc.weizmann.ac.il//pmbin/getpm?pmid=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://ispc.weizmann.ac.il//pmbin/getpm?pmid=15276842 15276842] | ||
[[Category: Protein complex]] | [[Category: Protein complex]] | ||
| - | [[Category: Chu, Y | + | [[Category: Chu, Y C.]] |
| - | [[Category: Hu, S | + | [[Category: Hu, S Q.]] |
| - | [[Category: Hua, Q | + | [[Category: Hua, Q X.]] |
[[Category: Huang, K.]] | [[Category: Huang, K.]] | ||
| - | [[Category: Katsoyannis, P | + | [[Category: Katsoyannis, P G.]] |
| - | [[Category: Meyts, P | + | [[Category: Meyts, P De.]] |
| - | [[Category: Nakagawa, S | + | [[Category: Nakagawa, S H.]] |
| - | [[Category: Weiss, M | + | [[Category: Weiss, M A.]] |
[[Category: Whittaker, J.]] | [[Category: Whittaker, J.]] | ||
[[Category: Xu, B.]] | [[Category: Xu, B.]] | ||
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[[Category: receptor binding]] | [[Category: receptor binding]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:08:54 2008'' |
Revision as of 13:08, 21 February 2008
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NMR STRUCTURE OF HUMAN INSULIN MUTANT HIS-B10-ASP, VAL-B12-ABA, PRO-B28-LYS, LYS-B29-PRO, 15 STRUCTURES
Contents |
Overview
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.
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
1T1Q is a Protein complex structure of sequences from [1]. Full crystallographic 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
Page seeded by OCA on Thu Feb 21 15:08:54 2008
