2h67

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{{Seed}}
 
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[[Image:2h67.png|left|200px]]
 
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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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The line below this paragraph, containing "STRUCTURE_2h67", creates the "Structure Box" on the page.
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<StructureSection load='2h67' size='340' side='right'caption='[[2h67]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''>
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You may change the PDB parameter (which sets the PDB file loaded into the applet)
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== Structural highlights ==
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or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
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<table><tr><td colspan='2'>[[2h67]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2H67 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2H67 FirstGlance]. <br>
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or leave the SCENE parameter empty for the default display.
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</td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">INS ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2h67 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2h67 OCA], [https://pdbe.org/2h67 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2h67 RCSB], [https://www.ebi.ac.uk/pdbsum/2h67 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2h67 ProSAT]</span></td></tr>
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{{STRUCTURE_2h67| PDB=2h67 | SCENE= }}
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</table>
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== Disease ==
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[[https://www.uniprot.org/uniprot/INS_HUMAN INS_HUMAN]] Defects in INS are the cause of familial hyperproinsulinemia (FHPRI) [MIM:[https://omim.org/entry/176730 176730]].<ref>PMID:3470784</ref> <ref>PMID:2196279</ref> <ref>PMID:4019786</ref> <ref>PMID:1601997</ref> Defects in INS are a cause of diabetes mellitus insulin-dependent type 2 (IDDM2) [MIM:[https://omim.org/entry/125852 125852]]. IDDM2 is a multifactorial disorder of glucose homeostasis that is characterized by susceptibility to ketoacidosis in the absence of insulin therapy. Clinical fetaures are polydipsia, polyphagia and polyuria which result from hyperglycemia-induced osmotic diuresis and secondary thirst. These derangements result in long-term complications that affect the eyes, kidneys, nerves, and blood vessels.<ref>PMID:18192540</ref> Defects in INS are a cause of diabetes mellitus permanent neonatal (PNDM) [MIM:[https://omim.org/entry/606176 606176]]. PNDM is a rare form of diabetes distinct from childhood-onset autoimmune diabetes mellitus type 1. It is characterized by insulin-requiring hyperglycemia that is diagnosed within the first months of life. Permanent neonatal diabetes requires lifelong therapy.<ref>PMID:17855560</ref> <ref>PMID:18162506</ref> Defects in INS are a cause of maturity-onset diabetes of the young type 10 (MODY10) [MIM:[https://omim.org/entry/613370 613370]]. MODY10 is a form of diabetes that is characterized by an autosomal dominant mode of inheritance, onset in childhood or early adulthood (usually before 25 years of age), a primary defect in insulin secretion and frequent insulin-independence at the beginning of the disease.<ref>PMID:18192540</ref> <ref>PMID:18162506</ref> <ref>PMID:20226046</ref>
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== Function ==
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[[https://www.uniprot.org/uniprot/INS_HUMAN INS_HUMAN]] Insulin decreases blood glucose concentration. It increases cell permeability to monosaccharides, amino acids and fatty acids. It accelerates glycolysis, the pentose phosphate cycle, and glycogen synthesis in liver.
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/h6/2h67_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2h67 ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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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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===NMR structure of human insulin mutant HIS-B5-ALA, HIS-B10-ASP PRO-B28-LYS, LYS-B29-PRO, 20 structures===
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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<ref>PMID:16728398</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 2h67" style="background-color:#fffaf0;"></div>
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==See Also==
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The line below this paragraph, {{ABSTRACT_PUBMED_16728398}}, adds the Publication Abstract to the page
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*[[Insulin 3D Structures|Insulin 3D Structures]]
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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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== References ==
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<references/>
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{{ABSTRACT_PUBMED_16728398}}
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__TOC__
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</StructureSection>
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==Disease==
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[[Category: Human]]
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Known disease associated with this structure: Diabetes mellitus, rare form OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176730 176730]], Hyperproinsulinemia, familial OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176730 176730]], MODY, one form OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176730 176730]]
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[[Category: Large Structures]]
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[[Category: Arvan, P]]
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==About this Structure==
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[[Category: Hu, S Q]]
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2H67 is a 2 chains 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].
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[[Category: Hua, Q X]]
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[[Category: Jia, W]]
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==Reference==
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[[Category: Liu, M]]
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<ref group="xtra">PMID:16728398</ref><references group="xtra"/>
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[[Category: Weiss, M A]]
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[[Category: Homo sapiens]]
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[[Category: Arvan, P.]]
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[[Category: Hu, S Q.]]
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[[Category: Hua, Q X.]]
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[[Category: Jia, W.]]
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[[Category: Liu, M.]]
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[[Category: Weiss, M A.]]
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[[Category: Hormone]]
[[Category: Hormone]]
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[[Category: Hormone-growth factor complex]]
[[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 Wed Feb 18 06:52:38 2009''
 

Current revision

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

PDB ID 2h67

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