2k9r: Difference between revisions

<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>

<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>

<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>

    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/k9/2k9r_consurf.spt"</scriptWhenChecked>

</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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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 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>

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<div class="pdbe-citations 2k9r" style="background-color:#fffaf0;"></div>

== References ==

<references/>

</StructureSection>

[[Category: Hu SQ]]

[[Category: Hua QX]]

[[Category: Huang K]]

[[Category: Jia WH]]

[[Category: Katsoyannis PG]]

[[Category: Nakarawa S]]

[[Category: Philips NFP]]

[[Category: Weiss MA]]

[[Category: Wittaker J]]

[[Category: Wittaker L]]

[[Category: Xu B]]