View source for 1zeg


==STRUCTURE OF B28 ASP INSULIN IN COMPLEX WITH PHENOL==
<StructureSection load='1zeg' size='340' side='right'caption='[[1zeg]], [[Resolution|resolution]] 1.60&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[1zeg]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1ZEG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1ZEG FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.6&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=IPH:PHENOL'>IPH</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1zeg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1zeg OCA], [https://pdbe.org/1zeg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1zeg RCSB], [https://www.ebi.ac.uk/pdbsum/1zeg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1zeg ProSAT]</span></td></tr>
</table>
== Disease ==
[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> 
== Function ==
[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.
== 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/ze/1zeg_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.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/main_output.php?pdb_ID=1zeg ConSurf].
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== Publication Abstract from PubMed ==
Insulin's natural tendency to form dimers and hexamers is significantly reduced in a mutant insulin B28 Pro --&gt; Asp, which has been designed as a monomeric, rapid-acting hormone for therapeutic purposes. This molecule can be induced to form zinc hexamers in the presence of small phenolic derivatives which are routinely used as antimicrobial agents in insulin preparations. Two structures of B28 Asp insulin have been determined from crystals grown in the presence of phenol and m-cresol. In these crystals, insulin exists as R6 zinc hexamers containing a number of phenol or m-cresol molecules associated with aromatic side chains at the dimer-dimer interfaces. At the monomer-monomer interfaces, the B28 Pro --&gt; Asp mutation leads to increased conformational flexibility in the B chain C termini, resulting in the loss of important intermolecular van der Waals contacts, thus explaining the monomeric character of B28 Asp insulin. The structure of a cross-linked derivative of B28 Asp insulin, containing an Ala-Lys dipeptide linker between residues B30 Ala and A1 Gly, has also determined. This forms an R6 zinc hexamer containing several m-cresol molecules. Of particular interest in this structure are two m-cresol molecules whose binding disrupted the beta-strand in one of the dimers. This observation suggests that the cross-link introduces mechanical strain on the B chain C terminus, thereby weakening the monomer-monomer interactions.

Interactions of phenol and m-cresol in the insulin hexamer, and their effect on the association properties of B28 pro --&gt; Asp insulin analogues.,Whittingham JL, Edwards DJ, Antson AA, Clarkson JM, Dodson GG Biochemistry. 1998 Aug 18;37(33):11516-23. PMID:9708987<ref>PMID:9708987</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 1zeg" style="background-color:#fffaf0;"></div>

==See Also==
*[[Insulin 3D Structures|Insulin 3D Structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Antson AA]]
[[Category: Clarkson JM]]
[[Category: Dodson GG]]
[[Category: Edwards EJ]]
[[Category: Whittingham JL]]