View source for 6veq


==Con-Ins G1 in complex with the human insulin microreceptor in turn in complex with Fv 83-7==
<StructureSection load='6veq' size='340' side='right'caption='[[6veq]], [[Resolution|resolution]] 3.25&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6veq]] is a 12 chain structure with sequence from [https://en.wikipedia.org/wiki/Conus_geographus Conus geographus], [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6VEQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6VEQ 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]] 3.25&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=CGU:GAMMA-CARBOXY-GLUTAMIC+ACID'>CGU</scene>, <scene name='pdbligand=CY3:2-AMINO-3-MERCAPTO-PROPIONAMIDE'>CY3</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=HYP:4-HYDROXYPROLINE'>HYP</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=6veq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6veq OCA], [https://pdbe.org/6veq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6veq RCSB], [https://www.ebi.ac.uk/pdbsum/6veq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6veq ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/INS1A_CONGE INS1A_CONGE] This venom insulin, from a fish-hunting cone snail, facilitates prey capture by rapidly inducing hypoglycemic shock (PubMed:25605914, PubMed:27617429). It is one of the smallest known insulin found in nature and lacks the C-terminal segment of the B chain that, in human insulin, mediates engagement of the insulin receptor (INSR) and assembly of the hormone's hexameric storage form (PubMed:27617429). Despite lacking this segment, it both binds and activates human insulin receptor (long isoform (HIR-B)) with a high potency (EC(50)=16.28 nM) (PubMed:30747102, PubMed:27617429). In vivo, intraperitoneal injection of this peptide into zebrafish lowers blood glucose with the same potency than human insulin (PubMed:25605914, PubMed:30747102). In addition, when applied to water, this peptide reduces overall locomotor activity of zebrafish larvae, observed as a significant decrease in the percentage of time spent swimming and movement frequency (PubMed:25605914). When tested on a mouse model of diabetes, this insulin also lowers blood glucose with a 10-fold lower potency than human insulin (PubMed:30747102).<ref>PMID:25605914</ref> <ref>PMID:27617429</ref> <ref>PMID:30747102</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Human insulin and its current therapeutic analogs all show propensity, albeit varyingly, to self-associate into dimers and hexamers, which delays their onset of action and makes blood glucose management difficult for people with diabetes. Recently, we described a monomeric, insulin-like peptide in cone-snail venom with moderate human insulin-like bioactivity. Here, with insights from structural biology studies, we report the development of mini-Ins-a human des-octapeptide insulin analog-as a structurally minimal, full-potency insulin. Mini-Ins is monomeric and, despite the lack of the canonical B-chain C-terminal octapeptide, has similar receptor binding affinity to human insulin. Four mutations compensate for the lack of contacts normally made by the octapeptide. Mini-Ins also has similar in vitro insulin signaling and in vivo bioactivities to human insulin. The full bioactivity of mini-Ins demonstrates the dispensability of the PheB24-PheB25-TyrB26 aromatic triplet and opens a new direction for therapeutic insulin development.

A structurally minimized yet fully active insulin based on cone-snail venom insulin principles.,Xiong X, Menting JG, Disotuar MM, Smith NA, Delaine CA, Ghabash G, Agrawal R, Wang X, He X, Fisher SJ, MacRaild CA, Norton RS, Gajewiak J, Forbes BE, Smith BJ, Safavi-Hemami H, Olivera B, Lawrence MC, Chou DH Nat Struct Mol Biol. 2020 Jun 1. pii: 10.1038/s41594-020-0430-8. doi:, 10.1038/s41594-020-0430-8. PMID:32483339<ref>PMID:32483339</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6veq" style="background-color:#fffaf0;"></div>

==See Also==
*[[Insulin 3D Structures|Insulin 3D Structures]]
*[[Insulin receptor 3D structures|Insulin receptor 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Conus geographus]]
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Mus musculus]]
[[Category: Chou DH-C]]
[[Category: Lawrence MC]]
[[Category: Menting JG]]
[[Category: Xiong X]]