2h67

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{{STRUCTURE_2h67| PDB=2h67 | SCENE= }}
{{STRUCTURE_2h67| PDB=2h67 | SCENE= }}
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'''NMR structure of human insulin mutant HIS-B5-ALA, HIS-B10-ASP PRO-B28-LYS, LYS-B29-PRO, 20 structures'''
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===NMR structure of human insulin mutant HIS-B5-ALA, HIS-B10-ASP PRO-B28-LYS, LYS-B29-PRO, 20 structures===
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==Overview==
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The insulins of eutherian mammals contain histidines at positions B5 and B10. The role of His(B10) is well defined: although not required in the mature hormone for receptor binding, in the islet beta cell this side chain functions in targeting proinsulin to glucose-regulated secretory granules and provides axial zincbinding sites in storage hexamers. In contrast, the role of His(B5) is less well understood. Here, we demonstrate that its substitution with Ala markedly impairs insulin chain combination in vitro and blocks the folding and secretion of human proinsulin in a transfected mammalian cell line. The structure and stability of an Ala(B5)-insulin analog were investigated in an engineered monomer (DKP-insulin). Despite its impaired foldability, the structure of the Ala(B5) analog retains a native-like T-state conformation. At the site of substitution, interchain nuclear Overhauser effects are observed between the methyl resonance of Ala(B5) and side chains in the A chain; these nuclear Overhauser effects resemble those characteristic of His(B5) in native insulin. Substantial receptor binding activity is retained (80 +/- 10% relative to the parent monomer). Although the thermodynamic stability of the Ala(B5) analog is decreased (DeltaDeltaG(u) = 1.7 +/- 0.1 kcal/mol), consistent with loss of His(B5)-related interchain packing and hydrogen bonds, control studies suggest that this decrement cannot account for its impaired foldability. We propose that nascent long-range interactions by His(B5) facilitate alignment of Cys(A7) and Cys(B7) in protein-folding intermediates; its conservation thus reflects mechanisms of oxidative folding rather than structure-function relationships in the native state.
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(as it appears on PubMed at http://www.pubmed.gov), where 16728398 is the PubMed ID number.
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{{ABSTRACT_PUBMED_16728398}}
==Disease==
==Disease==
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==About this Structure==
==About this Structure==
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2H67 is a [[Protein complex]] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2H67 OCA].
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2H67 is a [[Protein complex]] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2H67 OCA].
==Reference==
==Reference==
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[[Category: Human insulin]]
[[Category: Human insulin]]
[[Category: Mutant]]
[[Category: Mutant]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 05:54:49 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 29 13:38:36 2008''

Revision as of 10:38, 29 July 2008

Image:2h67.png

Template:STRUCTURE 2h67

Contents

NMR structure of human insulin mutant HIS-B5-ALA, HIS-B10-ASP PRO-B28-LYS, LYS-B29-PRO, 20 structures

Template:ABSTRACT PUBMED 16728398

Disease

Known disease associated with this structure: Diabetes mellitus, rare form OMIM:[176730], Hyperproinsulinemia, familial OMIM:[176730], MODY, one form OMIM:[176730]

About this Structure

2H67 is a Protein complex structure of sequences from Homo sapiens. Full experimental information is available from OCA.

Reference

A conserved histidine in insulin is required for the foldability of human proinsulin: structure and function of an ALAB5 analog., Hua QX, Liu M, Hu SQ, Jia W, Arvan P, Weiss MA, J Biol Chem. 2006 Aug 25;281(34):24889-99. Epub 2006 May 25. PMID:16728398

Page seeded by OCA on Tue Jul 29 13:38:36 2008

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