7nam
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | + | ==LRP6_E1 in complex with Lr-EET-3.5== | |
| + | <StructureSection load='7nam' size='340' side='right'caption='[[7nam]], [[Resolution|resolution]] 1.60Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[7nam]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7NAM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7NAM 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]] 1.6Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</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=7nam FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7nam OCA], [https://pdbe.org/7nam PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7nam RCSB], [https://www.ebi.ac.uk/pdbsum/7nam PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7nam ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Disease == | ||
| + | [https://www.uniprot.org/uniprot/LRP6_HUMAN LRP6_HUMAN] Coronary artery disease - hyperlipidemia - hypertension - diabetes - osteoporosis. The disease is caused by mutations affecting the gene represented in this entry. | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/LRP6_HUMAN LRP6_HUMAN] Component of the Wnt-Fzd-LRP5-LRP6 complex that triggers beta-catenin signaling through inducing aggregation of receptor-ligand complexes into ribosome-sized signalsomes. Cell-surface coreceptor of Wnt/beta-catenin signaling, which plays a pivotal role in bone formation. The Wnt-induced Fzd/LRP6 coreceptor complex recruits DVL1 polymers to the plasma membrane which, in turn, recruits the AXIN1/GSK3B-complex to the cell surface promoting the formation of signalsomes and inhibiting AXIN1/GSK3-mediated phosphorylation and destruction of beta-catenin. Required for posterior patterning of the epiblast during gastrulation (By similarity).<ref>PMID:11448771</ref> <ref>PMID:11357136</ref> <ref>PMID:15778503</ref> <ref>PMID:16341017</ref> <ref>PMID:16513652</ref> <ref>PMID:17400545</ref> <ref>PMID:17326769</ref> <ref>PMID:19107203</ref> <ref>PMID:19801552</ref> <ref>PMID:19293931</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Developing peptide-based tools to fine-tune growth signaling pathways, in particular molecules with exquisite selectivity and high affinities, opens up opportunities for cellular reprogramming in tissue regeneration. Here, we present a library based on cystine-knot peptides (CKPs) that incorporate multiple loops for randomization and selection via directed evolution. Resulting binders could be assembled into multimeric structures to fine-tune cellular signaling. An example is presented for the Wnt pathway, which plays a key role in the homeostasis and regeneration of tissues such as lung, skin, and intestine. We discovered picomolar affinity CKP agonists of the human LPR6 receptor by exploring the limits of the topological manipulation of LRP6 dimerization. Structural analyses revealed that the agonists bind at the first beta-propeller domain of LRP6, mimicking the natural Wnt inhibitors DKK1 and SOST. However, the CKP agonists exhibit a different mode of action as they amplify the signaling of natural Wnt ligands but do not activate the pathway by themselves. In an alveolosphere organoid model, the CKP agonists induced alveolar stem cell activity. They also stimulated growth in primary human intestinal organoids. The approach described here advances the important frontier of next-generation agonist design and could be applied to other signaling pathways to discover tunable agonist ligands. | ||
| - | + | Directed evolution identifies high-affinity cystine-knot peptide agonists and antagonists of Wnt/beta-catenin signaling.,Hansen S, Zhang Y, Hwang S, Nabhan A, Li W, Fuhrmann J, Kschonsak Y, Zhou L, Nile AH, Gao X, Piskol R, de Sousa E Melo F, de Sauvage FJ, Hannoush RN Proc Natl Acad Sci U S A. 2022 Nov 16;119(46):e2207327119. doi: , 10.1073/pnas.2207327119. Epub 2022 Nov 7. PMID:36343233<ref>PMID:36343233</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 7nam" style="background-color:#fffaf0;"></div> | ||
| + | |||
| + | ==See Also== | ||
| + | *[[Trypsin inhibitor 3D structures|Trypsin inhibitor 3D structures]] | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Synthetic construct]] | ||
| + | [[Category: Hannoush RN]] | ||
| + | [[Category: Hansen S]] | ||
Current revision
LRP6_E1 in complex with Lr-EET-3.5
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