6o9c
From Proteopedia
(Difference between revisions)
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<StructureSection load='6o9c' size='340' side='right'caption='[[6o9c]], [[Resolution|resolution]] 2.45Å' scene=''> | <StructureSection load='6o9c' size='340' side='right'caption='[[6o9c]], [[Resolution|resolution]] 2.45Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>[[6o9c]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6O9C OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6O9C FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6o9c]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6O9C OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6O9C FirstGlance]. <br> |
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | ||
| + | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">HLA-A, HLAA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), B2M, CDABP0092, HDCMA22P ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), CTNNB1, CTNNB, OK/SW-cl.35, PRO2286 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=6o9c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6o9c OCA], [http://pdbe.org/6o9c PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6o9c RCSB], [http://www.ebi.ac.uk/pdbsum/6o9c PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6o9c 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=6o9c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6o9c OCA], [http://pdbe.org/6o9c PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6o9c RCSB], [http://www.ebi.ac.uk/pdbsum/6o9c PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6o9c ProSAT]</span></td></tr> | ||
</table> | </table> | ||
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== Function == | == Function == | ||
[[http://www.uniprot.org/uniprot/1A03_HUMAN 1A03_HUMAN]] Involved in the presentation of foreign antigens to the immune system. [[http://www.uniprot.org/uniprot/CTNB1_HUMAN CTNB1_HUMAN]] Key downstream component of the canonical Wnt signaling pathway. In the absence of Wnt, forms a complex with AXIN1, AXIN2, APC, CSNK1A1 and GSK3B that promotes phosphorylation on N-terminal Ser and Thr residues and ubiquitination of CTNNB1 via BTRC and its subsequent degradation by the proteasome. In the presence of Wnt ligand, CTNNB1 is not ubiquitinated and accumulates in the nucleus, where it acts as a coactivator for transcription factors of the TCF/LEF family, leading to activate Wnt responsive genes. Involved in the regulation of cell adhesion. Acts as a negative regulator of centrosome cohesion. Involved in the CDK2/PTPN6/CTNNB1/CEACAM1 pathway of insulin internalization. Blocks anoikis of malignant kidney and intestinal epithelial cells and promotes their anchorage-independent growth by down-regulating DAPK2.<ref>PMID:17524503</ref> <ref>PMID:18086858</ref> <ref>PMID:18957423</ref> <ref>PMID:21262353</ref> [[http://www.uniprot.org/uniprot/B2MG_HUMAN B2MG_HUMAN]] Component of the class I major histocompatibility complex (MHC). Involved in the presentation of peptide antigens to the immune system. | [[http://www.uniprot.org/uniprot/1A03_HUMAN 1A03_HUMAN]] Involved in the presentation of foreign antigens to the immune system. [[http://www.uniprot.org/uniprot/CTNB1_HUMAN CTNB1_HUMAN]] Key downstream component of the canonical Wnt signaling pathway. In the absence of Wnt, forms a complex with AXIN1, AXIN2, APC, CSNK1A1 and GSK3B that promotes phosphorylation on N-terminal Ser and Thr residues and ubiquitination of CTNNB1 via BTRC and its subsequent degradation by the proteasome. In the presence of Wnt ligand, CTNNB1 is not ubiquitinated and accumulates in the nucleus, where it acts as a coactivator for transcription factors of the TCF/LEF family, leading to activate Wnt responsive genes. Involved in the regulation of cell adhesion. Acts as a negative regulator of centrosome cohesion. Involved in the CDK2/PTPN6/CTNNB1/CEACAM1 pathway of insulin internalization. Blocks anoikis of malignant kidney and intestinal epithelial cells and promotes their anchorage-independent growth by down-regulating DAPK2.<ref>PMID:17524503</ref> <ref>PMID:18086858</ref> <ref>PMID:18957423</ref> <ref>PMID:21262353</ref> [[http://www.uniprot.org/uniprot/B2MG_HUMAN B2MG_HUMAN]] Component of the class I major histocompatibility complex (MHC). Involved in the presentation of peptide antigens to the immune system. | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Mutations in CTNNB1, the gene encoding beta-catenin, are common in colon and liver cancers, the most frequent mutation affecting Ser-45 in beta-catenin. Peptides derived from wild-type beta-catenin have previously been shown to be presented on the cell surface as part of Major Histocompatibility Complex (MHC) Class I, suggesting an opportunity for targeting this common driver gene mutation with antibody-based therapies. Here, crystal structures of both the wild-type and S45F mutant peptide bound to HLA-A*03:01 at 2.20 and 2.45 A resolutions, respectively, confirmed the accessibility of the phenylalanine residue for antibody recognition. Phage display was then used to identify single chain variable fragment clones that selectively bind the S45F mutant peptide presented in HLA-A*03:01 and have minimal wild-type or other off-target binding. Following initial characterization of five clones, we selected a single clone, E10, for further investigation. We developed a computational model of the binding of E10 to the mutant peptide bound HLA-A3, incorporating data from affinity maturation as initial validation. In the future, our model may be used to design clones with maintained specificity and higher affinity. Such derivatives could be adapted into either cell-based (CAR-T) or protein-based (bispecific T-cell engagers) therapies to target cancer cells harboring the S45F mutation in CTNNB1. | ||
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| + | An engineered antibody fragment targeting mutant beta-catenin via Major Histocompatibility Complex I neoantigen presentation.,Miller MS, Douglass J, Hwang MS, Skora AD, Murphy M, Papadopoulos N, Kinzler KW, Vogelstein B, Zhou S, Gabelli SB J Biol Chem. 2019 Nov 5. pii: RA119.010251. doi: 10.1074/jbc.RA119.010251. PMID:31690625<ref>PMID:31690625</ref> | ||
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| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 6o9c" style="background-color:#fffaf0;"></div> | ||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[Category: Human]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Gabelli, S B]] | [[Category: Gabelli, S B]] | ||
Revision as of 17:42, 20 November 2019
Crystal structure of HLA-A3*01 in complex with a mutant beta-catenin peptide
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