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| | <StructureSection load='6ne1' size='340' side='right'caption='[[6ne1]], [[Resolution|resolution]] 3.01Å' scene=''> | | <StructureSection load='6ne1' size='340' side='right'caption='[[6ne1]], [[Resolution|resolution]] 3.01Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6ne1]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Aspfu Aspfu] and [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6NE1 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6NE1 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6ne1]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Aspergillus_fumigatus_Af293 Aspergillus fumigatus Af293] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6NE1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6NE1 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.011Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6ndz|6ndz]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">FZD4 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), AFUA_1G01020 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=330879 ASPFU])</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=6ne1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ne1 OCA], [https://pdbe.org/6ne1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ne1 RCSB], [https://www.ebi.ac.uk/pdbsum/6ne1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ne1 ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6ne1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ne1 OCA], [http://pdbe.org/6ne1 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ne1 RCSB], [http://www.ebi.ac.uk/pdbsum/6ne1 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ne1 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/FZD4_HUMAN FZD4_HUMAN]] Retinopathy of prematurity;Familial exudative vitreoretinopathy;Persistent hyperplastic primary vitreous. The disease is caused by mutations affecting the gene represented in this entry. | + | [https://www.uniprot.org/uniprot/FZD4_HUMAN FZD4_HUMAN] Retinopathy of prematurity;Familial exudative vitreoretinopathy;Persistent hyperplastic primary vitreous. The disease is caused by mutations affecting the gene represented in this entry. |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/FZD4_HUMAN FZD4_HUMAN]] Receptor for Wnt proteins. Most of frizzled receptors are coupled to the beta-catenin (CTNNB1) canonical signaling pathway, which leads to the activation of disheveled proteins, inhibition of GSK-3 kinase, nuclear accumulation of beta-catenin (CTNNB1) and activation of Wnt target genes. Plays a critical role in retinal vascularization by acting as a receptor for Wnt proteins and norrin (NDP). In retina, it can be both activated by Wnt protein-binding, but also by a Wnt-independent signaling via binding of norrin (NDP), promoting in both cases beta-catenin (CTNNB1) accumulation and stimulation of LEF/TCF-mediated transcriptional programs. A second signaling pathway involving PKC and calcium fluxes has been seen for some family members, but it is not yet clear if it represents a distinct pathway or if it can be integrated in the canonical pathway, as PKC seems to be required for Wnt-mediated inactivation of GSK-3 kinase. Both pathways seem to involve interactions with G-proteins. May be involved in transduction and intercellular transmission of polarity information during tissue morphogenesis and/or in differentiated tissues. | + | [https://www.uniprot.org/uniprot/FZD4_HUMAN FZD4_HUMAN] Receptor for Wnt proteins. Most of frizzled receptors are coupled to the beta-catenin (CTNNB1) canonical signaling pathway, which leads to the activation of disheveled proteins, inhibition of GSK-3 kinase, nuclear accumulation of beta-catenin (CTNNB1) and activation of Wnt target genes. Plays a critical role in retinal vascularization by acting as a receptor for Wnt proteins and norrin (NDP). In retina, it can be both activated by Wnt protein-binding, but also by a Wnt-independent signaling via binding of norrin (NDP), promoting in both cases beta-catenin (CTNNB1) accumulation and stimulation of LEF/TCF-mediated transcriptional programs. A second signaling pathway involving PKC and calcium fluxes has been seen for some family members, but it is not yet clear if it represents a distinct pathway or if it can be integrated in the canonical pathway, as PKC seems to be required for Wnt-mediated inactivation of GSK-3 kinase. Both pathways seem to involve interactions with G-proteins. May be involved in transduction and intercellular transmission of polarity information during tissue morphogenesis and/or in differentiated tissues. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Aspfu]] | + | [[Category: Aspergillus fumigatus Af293]] |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Garcia, K C]] | + | [[Category: Garcia KC]] |
| - | [[Category: Jude, K M]] | + | [[Category: Jude KM]] |
| - | [[Category: Miao, Y]] | + | [[Category: Miao Y]] |
| - | [[Category: Biosynthetic protein]]
| + | |
| - | [[Category: Biosynthetic protein-signaling protein complex]]
| + | |
| - | [[Category: Designed protein]]
| + | |
| - | [[Category: Frizzled]]
| + | |
| Structural highlights
Disease
FZD4_HUMAN Retinopathy of prematurity;Familial exudative vitreoretinopathy;Persistent hyperplastic primary vitreous. The disease is caused by mutations affecting the gene represented in this entry.
Function
FZD4_HUMAN Receptor for Wnt proteins. Most of frizzled receptors are coupled to the beta-catenin (CTNNB1) canonical signaling pathway, which leads to the activation of disheveled proteins, inhibition of GSK-3 kinase, nuclear accumulation of beta-catenin (CTNNB1) and activation of Wnt target genes. Plays a critical role in retinal vascularization by acting as a receptor for Wnt proteins and norrin (NDP). In retina, it can be both activated by Wnt protein-binding, but also by a Wnt-independent signaling via binding of norrin (NDP), promoting in both cases beta-catenin (CTNNB1) accumulation and stimulation of LEF/TCF-mediated transcriptional programs. A second signaling pathway involving PKC and calcium fluxes has been seen for some family members, but it is not yet clear if it represents a distinct pathway or if it can be integrated in the canonical pathway, as PKC seems to be required for Wnt-mediated inactivation of GSK-3 kinase. Both pathways seem to involve interactions with G-proteins. May be involved in transduction and intercellular transmission of polarity information during tissue morphogenesis and/or in differentiated tissues.
Publication Abstract from PubMed
To discriminate between closely related members of a protein family that differ at a limited number of spatially distant positions is a challenge for drug discovery. We describe a combined computational design and experimental selection approach for generating binders targeting functional sites with large, shape complementary interfaces to read out subtle sequence differences for subtype-specific antagonism. Repeat proteins are computationally docked against a functionally relevant region of the target protein surface that varies in the different subtypes, and the interface sequences are optimized for affinity and specificity first computationally and then experimentally. We used this approach to generate a series of human Frizzled (Fz) subtype-selective antagonists with extensive shape complementary interaction surfaces considerably larger than those of repeat proteins selected from random libraries. In vivo administration revealed that Wnt-dependent pericentral liver gene expression involves multiple Fz subtypes, while maintenance of the intestinal crypt stem cell compartment involves only a limited subset.
Receptor subtype discrimination using extensive shape complementary designed interfaces.,Dang LT, Miao Y, Ha A, Yuki K, Park K, Janda CY, Jude KM, Mohan K, Ha N, Vallon M, Yuan J, Vilches-Moure JG, Kuo CJ, Garcia KC, Baker D Nat Struct Mol Biol. 2019 May 13. pii: 10.1038/s41594-019-0224-z. doi:, 10.1038/s41594-019-0224-z. PMID:31086346[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Dang LT, Miao Y, Ha A, Yuki K, Park K, Janda CY, Jude KM, Mohan K, Ha N, Vallon M, Yuan J, Vilches-Moure JG, Kuo CJ, Garcia KC, Baker D. Receptor subtype discrimination using extensive shape complementary designed interfaces. Nat Struct Mol Biol. 2019 May 13. pii: 10.1038/s41594-019-0224-z. doi:, 10.1038/s41594-019-0224-z. PMID:31086346 doi:http://dx.doi.org/10.1038/s41594-019-0224-z
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