View source for 1guj

==INSULIN AT PH 2: STRUCTURAL ANALYSIS OF THE CONDITIONS PROMOTING INSULIN FIBRE FORMATION.==
<StructureSection load='1guj' size='340' side='right' caption='[[1guj]], [[Resolution|resolution]] 1.62&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[1guj]] is a 4 chain structure with sequence 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=1GUJ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1GUJ FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1a7f|1a7f]], [[1ai0|1ai0]], [[1aiy|1aiy]], [[1b9e|1b9e]], [[1ben|1ben]], [[1hiq|1hiq]], [[1his|1his]], [[1hit|1hit]], [[1hls|1hls]], [[1htv|1htv]], [[1hui|1hui]], [[1iog|1iog]], [[1ioh|1ioh]], [[1j73|1j73]], [[1jca|1jca]], [[1jco|1jco]], [[1k3m|1k3m]], [[1lph|1lph]], [[1mhi|1mhi]], [[1mhj|1mhj]], [[1qiy|1qiy]], [[1qiz|1qiz]], [[1qj0|1qj0]], [[1sjt|1sjt]], [[1sju|1sju]], [[1trz|1trz]], [[1tyl|1tyl]], [[1tym|1tym]], [[1vks|1vks]], [[1vkt|1vkt]], [[1xda|1xda]], [[1xgl|1xgl]], [[1zeg|1zeg]], [[1zeh|1zeh]], [[1znj|1znj]], [[2aiy|2aiy]], [[2hiu|2hiu]], [[3aiy|3aiy]], [[4aiy|4aiy]], [[5aiy|5aiy]]</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1guj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1guj OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1guj RCSB], [http://www.ebi.ac.uk/pdbsum/1guj PDBsum]</span></td></tr>
</table>
== Disease ==
[[http://www.uniprot.org/uniprot/INS_HUMAN INS_HUMAN]] Defects in INS are the cause of familial hyperproinsulinemia (FHPRI) [MIM:[http://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:[http://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:[http://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:[http://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>  
== Function ==
[[http://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. 
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/gu/1guj_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</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/chain_selection.php?pdb_ID=2ata ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
When insulin solutions are subjected to acid, heat and agitation, the normal pattern of insulin assembly (dimers--&gt;tetramers--&gt;hexamers) is disrupted; the molecule undergoes conformational changes allowing it to follow an alternative aggregation pathway (via a monomeric species) leading to the formation of insoluble amyloid fibres. To investigate the effect of acid pH on the conformation and aggregation state of the protein, the crystal structure of human insulin at pH 2.1 has been determined to 1.6 A resolution. The structure reveals that the native fold is maintained at low pH, and that the molecule is still capable of forming dimers similar to those found in hexameric insulin structures at higher pH. Sulphate ions are incorporated into the molecule and the crystal lattice where they neutralise positive charges on the protein, stabilising its structure and facilitating crystallisation. The sulphate interactions are associated with local deformations in the protein, which may indicate that the structure is more plastic at low pH. Transmission electron microscopy analysis of insulin fibres reveals that the appearance of the fibres is greatly influenced by the type of acid employed. Sulphuric acid produces distinctive highly bunched, truncated fibres, suggesting that the sulphate ions have a sophisticated role to play in fibre formation, rather as they do in the crystal structure. Analytical ultracentrifugation studies show that in the absence of heating, insulin is predominantly dimeric in mineral acids, whereas in acetic acid the equilibrium is shifted towards the monomer. Hence, the effect of acid on the aggregation state of insulin is also complex. These results suggest that acid conditions increase the susceptibility of the molecule to conformational change and dissociation, and enhance the rate of fibrillation by providing a charged environment in which the attractive forces between the protein molecules is increased.

Insulin at pH 2: structural analysis of the conditions promoting insulin fibre formation.,Whittingham JL, Scott DJ, Chance K, Wilson A, Finch J, Brange J, Guy Dodson G J Mol Biol. 2002 Apr 26;318(2):479-90. PMID:12051853<ref>PMID:12051853</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>

==See Also==
*[[Molecular Playground/Insulin|Molecular Playground/Insulin]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Brange, J]]
[[Category: Chance, K]]
[[Category: Dodson, G G]]
[[Category: Finch, J]]
[[Category: Scott, D J]]
[[Category: Whittingham, J L]]
[[Category: Wilson, A]]
[[Category: Hormone]]
[[Category: Low ph]]
[[Category: Metabolic role]]
[[Category: Sulphate ion]]