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Structure-activity relationship studies of allosteric inhibitors of EYA2 tyrosine phosphataseStructure-activity relationship studies of allosteric inhibitors of EYA2 tyrosine phosphatase
Structural highlights
FunctionEYA2_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 PubMedHuman 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
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