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[[Image:2k91.jpg|left|200px]]


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==Enhancing the activity of insulin by stereospecific unfolding==
The line below this paragraph, containing "STRUCTURE_2k91", creates the "Structure Box" on the page.
<StructureSection load='2k91' size='340' side='right'caption='[[2k91]]' scene=''>
You may change the PDB parameter (which sets the PDB file loaded into the applet)  
== Structural highlights ==
or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
<table><tr><td colspan='2'>[[2k91]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2K91 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2K91 FirstGlance]. <br>
or leave the SCENE parameter empty for the default display.
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR, 20 models</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=2k91 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2k91 OCA], [https://pdbe.org/2k91 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2k91 RCSB], [https://www.ebi.ac.uk/pdbsum/2k91 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2k91 ProSAT]</span></td></tr>
{{STRUCTURE_2k91|  PDB=2k91  |  SCENE=  }}
</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.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
A central tenet of molecular biology holds that the function of a protein is mediated by its structure. An inactive ground-state conformation may nonetheless be enjoined by the interplay of competing biological constraints. A model is provided by insulin, well characterized at atomic resolution by x-ray crystallography. Here, we demonstrate that the activity of the hormone is enhanced by stereospecific unfolding of a conserved structural element. A bifunctional beta-strand mediates both self-assembly (within beta-cell storage vesicles) and receptor binding (in the bloodstream). This strand is anchored by an invariant side chain (Phe(B24)); its substitution by Ala leads to an unstable but native-like analog of low activity. Substitution by d-Ala is equally destabilizing, and yet the protein diastereomer exhibits enhanced activity with segmental unfolding of the beta-strand. Corresponding photoactivable derivatives (containing l- or d-para-azido-Phe) cross-link to the insulin receptor with higher d-specific efficiency. Aberrant exposure of hydrophobic surfaces in the analogs is associated with accelerated fibrillation, a form of aggregation-coupled misfolding associated with cellular toxicity. Conservation of Phe(B24), enforced by its dual role in native self-assembly and induced fit, thus highlights the implicit role of misfolding as an evolutionary constraint. Whereas classical crystal structures of insulin depict its storage form, signaling requires engagement of a detachable arm at an extended receptor interface. Because this active conformation resembles an amyloidogenic intermediate, we envisage that induced fit and self-assembly represent complementary molecular adaptations to potential proteotoxicity. The cryptic threat of misfolding poses a universal constraint in the evolution of polypeptide sequences.


===Enhancing the activity of insulin by stereospecific unfolding===
Enhancing the activity of a protein by stereospecific unfolding: conformational life cycle of insulin and its evolutionary origins.,Hua QX, Xu B, Huang K, Hu SQ, Nakagawa S, Jia W, Wang S, Whittaker J, Katsoyannis PG, Weiss MA J Biol Chem. 2009 May 22;284(21):14586-96. Epub 2009 Mar 25. PMID:19321436<ref>PMID:19321436</ref>


From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 2k91" style="background-color:#fffaf0;"></div>


==About this Structure==
==See Also==
2K91 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=2K91 OCA].
*[[Insulin 3D Structures|Insulin 3D Structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Hu, S Q.]]
[[Category: Large Structures]]
[[Category: Hua, Q X.]]
[[Category: Hu SQ]]
[[Category: Huang, K.]]
[[Category: Hua QX]]
[[Category: Jia, W H.]]
[[Category: Huang K]]
[[Category: Katsoyannis, P G.]]
[[Category: Jia WH]]
[[Category: Nakarawa, S.]]
[[Category: Katsoyannis PG]]
[[Category: Philips, N F.P.]]
[[Category: Nakarawa S]]
[[Category: Weiss, M A.]]
[[Category: Philips NFP]]
[[Category: Wittaker, J.]]
[[Category: Weiss MA]]
[[Category: Wittaker, L.]]
[[Category: Wittaker J]]
[[Category: Xu, B.]]
[[Category: Wittaker L]]
[[Category: Carbohydrate metabolism]]
[[Category: Xu B]]
[[Category: Cleavage on pair of basic residue]]
[[Category: Diabetes mellitus]]
[[Category: Disease mutation]]
[[Category: Glucose metabolism]]
[[Category: Hormone]]
[[Category: Insulin]]
[[Category: Mutant]]
[[Category: Pharmaceutical]]
[[Category: Secreted]]
 
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Retrieved from "https://proteopedia.org/2k91"