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| | <StructureSection load='7f8h' size='340' side='right'caption='[[7f8h]], [[Resolution|resolution]] 3.30Å' scene=''> | | <StructureSection load='7f8h' size='340' side='right'caption='[[7f8h]], [[Resolution|resolution]] 3.30Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[7f8h]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7F8H OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7F8H FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7f8h]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7F8H OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7F8H FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1SI:3-fluoranyl-~{N}-[(~{E})-(5-pyridin-2-ylsulfanylfuran-2-yl)methylideneamino]benzamide'>1SI</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]] 3.3Å</td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Protein-tyrosine-phosphatase Protein-tyrosine-phosphatase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.3.48 3.1.3.48] </span></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1SI:3-fluoranyl-~{N}-[(~{E})-(5-pyridin-2-ylsulfanylfuran-2-yl)methylideneamino]benzamide'>1SI</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=7f8h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7f8h OCA], [https://pdbe.org/7f8h PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7f8h RCSB], [https://www.ebi.ac.uk/pdbsum/7f8h PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7f8h ProSAT]</span></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=7f8h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7f8h OCA], [https://pdbe.org/7f8h PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7f8h RCSB], [https://www.ebi.ac.uk/pdbsum/7f8h PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7f8h ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[https://www.uniprot.org/uniprot/EYA2_HUMAN EYA2_HUMAN]] Tyrosine phosphatase that specifically dephosphorylates 'Tyr-142' of histone H2AX (H2AXY142ph). 'Tyr-142' phosphorylation of histone H2AX plays a central role in DNA repair and acts as a mark that distinguishes between apoptotic and repair responses to genotoxic stress. Promotes efficient DNA repair by dephosphorylating H2AX, promoting the recruitment of DNA repair complexes containing MDC1. Its function as histone phosphatase probably explains its role in transcription regulation during organogenesis. Coactivates SIX1. Seems to coactivate SIX2, SIX4 and SIX5. Together with SIX1 and DACH2 seem to be involved in myogenesis. May be involved in development of the eye. Interaction with GNAZ and GNAI2 prevents nuclear translocation and transcriptional activity.<ref>PMID:19351884</ref>
| + | [https://www.uniprot.org/uniprot/EYA2_HUMAN EYA2_HUMAN] Tyrosine phosphatase that specifically dephosphorylates 'Tyr-142' of histone H2AX (H2AXY142ph). 'Tyr-142' phosphorylation of histone H2AX plays a central role in DNA repair and acts as a mark that distinguishes between apoptotic and repair responses to genotoxic stress. Promotes efficient DNA repair by dephosphorylating H2AX, promoting the recruitment of DNA repair complexes containing MDC1. Its function as histone phosphatase probably explains its role in transcription regulation during organogenesis. Coactivates SIX1. Seems to coactivate SIX2, SIX4 and SIX5. Together with SIX1 and DACH2 seem to be involved in myogenesis. May be involved in development of the eye. Interaction with GNAZ and GNAI2 prevents nuclear translocation and transcriptional activity.<ref>PMID:19351884</ref> |
| | <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: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Protein-tyrosine-phosphatase]]
| + | [[Category: Anantharajan J]] |
| - | [[Category: Anantharajan, J]] | + | [[Category: Baburajendran N]] |
| - | [[Category: Baburajendran, N]] | + | |
| - | [[Category: Eya2]]
| + | |
| - | [[Category: Eyes absent protein]]
| + | |
| - | [[Category: Phosphatase]]
| + | |
| - | [[Category: Transcription]]
| + | |
| - | [[Category: Transcription coactivator]]
| + | |
| Structural highlights
Function
EYA2_HUMAN Tyrosine phosphatase that specifically dephosphorylates 'Tyr-142' of histone H2AX (H2AXY142ph). 'Tyr-142' phosphorylation of histone H2AX plays a central role in DNA repair and acts as a mark that distinguishes between apoptotic and repair responses to genotoxic stress. Promotes efficient DNA repair by dephosphorylating H2AX, promoting the recruitment of DNA repair complexes containing MDC1. Its function as histone phosphatase probably explains its role in transcription regulation during organogenesis. Coactivates SIX1. Seems to coactivate SIX2, SIX4 and SIX5. Together with SIX1 and DACH2 seem to be involved in myogenesis. May be involved in development of the eye. Interaction with GNAZ and GNAI2 prevents nuclear translocation and transcriptional activity.[1]
Publication Abstract from PubMed
Human eyes absent (EYA) proteins possess Tyr phosphatase activity, which is critical for numerous cancer and metastasis promoting activities, making it an attractive target for cancer therapy. In this work, we demonstrate that the inhibitor-bound form of EYA2 does not favour binding to Mg(2+) , which is indispensable for the Tyr phosphatase activity. We further describe characterization and optimization of this class of allosteric inhibitors. A series of analogues were synthesized to improve potency of the inhibitors and to elucidate structure-activity relationships. Two co-crystal structures confirm the binding modes of this class of inhibitors. Our medicinal chemical, structural, biochemical, and biophysical studies provide insight into the molecular interactions of EYA2 with these allosteric inhibitors. The compounds derived from this study are useful for exploring the function of the Tyr phosphatase activity of EYA2 in normal and cancerous cells and serve as reference compounds for screening or developing allosteric phosphatase inhibitors. Finally, the co-crystal structures reported in this study will aid in structure-based drug discovery against EYA2.
Structure-activity relationship studies of allosteric inhibitors of EYA2 tyrosine phosphatase.,Anantharajan J, Baburajendran N, Lin G, Loh YY, Xu W, Ahmad NHB, Liu S, Jasson AE, Kuan JWL, Ng EY, Yeo YK, Hung AW, Joy J, Hill J, Ford HL, Zhao R, Keller TH, Kang C Protein Sci. 2021 Nov 11. doi: 10.1002/pro.4234. PMID:34761455[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Krishnan N, Jeong DG, Jung SK, Ryu SE, Xiao A, Allis CD, Kim SJ, Tonks NK. Dephosphorylation of the C-terminal tyrosyl residue of the DNA damage-related histone H2A.X is mediated by the protein phosphatase eyes absent. J Biol Chem. 2009 Jun 12;284(24):16066-70. Epub 2009 Apr 7. PMID:19351884 doi:C900032200
- ↑ Anantharajan J, Baburajendran N, Lin G, Loh YY, Xu W, Ahmad NHB, Liu S, Jasson AE, Kuan JWL, Ng EY, Yeo YK, Hung AW, Joy J, Hill J, Ford HL, Zhao R, Keller TH, Kang C. Structure-activity relationship studies of allosteric inhibitors of EYA2 tyrosine phosphatase. Protein Sci. 2021 Nov 11. doi: 10.1002/pro.4234. PMID:34761455 doi:http://dx.doi.org/10.1002/pro.4234
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