2k9r

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{{Seed}}
 
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[[Image:2k9r.png|left|200px]]
 
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==Enhancing the activity of insulin by stereospecific unfolding==
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The line below this paragraph, containing "STRUCTURE_2k9r", creates the "Structure Box" on the page.
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<StructureSection load='2k9r' size='340' side='right'caption='[[2k9r]]' 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'>[[2k9r]] 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=2K9R OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2K9R FirstGlance]. <br>
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or leave the SCENE parameter empty for the default display.
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</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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DAL:D-ALANINE'>DAL</scene></td></tr>
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{{STRUCTURE_2k9r| PDB=2k9r | SCENE= }}
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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=2k9r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2k9r OCA], [https://pdbe.org/2k9r PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2k9r RCSB], [https://www.ebi.ac.uk/pdbsum/2k9r PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2k9r ProSAT]</span></td></tr>
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</table>
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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/k9/2k9r_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.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=2k9r 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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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.
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===Enhancing the activity of insulin by stereospecific unfolding===
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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>
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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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The line below this paragraph, {{ABSTRACT_PUBMED_19321436}}, adds the Publication Abstract to the page
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<div class="pdbe-citations 2k9r" style="background-color:#fffaf0;"></div>
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(as it appears on PubMed at http://www.pubmed.gov), where 19321436 is the PubMed ID number.
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== References ==
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<references/>
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{{ABSTRACT_PUBMED_19321436}}
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__TOC__
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</StructureSection>
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==Disease==
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Known disease associated with this structure: Hyperproinsulinemia, familial, with or without diabetes OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176730 176730]]
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==About this Structure==
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2K9R 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=2K9R OCA].
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==Reference==
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<ref group="xtra">PMID:19321436</ref><references group="xtra"/>
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[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Hu, S Q.]]
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[[Category: Large Structures]]
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[[Category: Hua, Q X.]]
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[[Category: Hu SQ]]
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[[Category: Huang, K.]]
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[[Category: Hua QX]]
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[[Category: Jia, W H.]]
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[[Category: Huang K]]
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[[Category: Katsoyannis, P G.]]
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[[Category: Jia WH]]
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[[Category: Nakarawa, S.]]
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[[Category: Katsoyannis PG]]
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[[Category: Philips, N F.P.]]
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[[Category: Nakarawa S]]
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[[Category: Weiss, M A.]]
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[[Category: Philips NFP]]
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[[Category: Wittaker, J.]]
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[[Category: Weiss MA]]
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[[Category: Wittaker, L.]]
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[[Category: Wittaker J]]
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[[Category: Xu, B.]]
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[[Category: Wittaker L]]
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[[Category: Carbohydrate metabolism]]
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[[Category: Xu B]]
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[[Category: Cleavage on pair of basic residue]]
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[[Category: Diabetes mellitus]]
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[[Category: Disease mutation]]
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[[Category: Glucose metabolism]]
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[[Category: Hormone]]
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[[Category: Insulin]]
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[[Category: Mutant]]
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[[Category: Pharmaceutical]]
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[[Category: Secreted]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jun 3 09:32:58 2009''
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Current revision

Enhancing the activity of insulin by stereospecific unfolding

PDB ID 2k9r

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