5zma
Structural basis for an allosteric Eya2 phosphatase inhibitor
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 PubMedEya proteins (EYA1-4) are critical developmental transcriptional cofactors that contain an Eya domain (ED) harboring Tyr phosphatase activity. Eya proteins are largely downregulated post-embryogenesis but are re-expressed in cancers, and their Tyr phosphatase activity plays an important role in the DNA damage response and tumor progression. We previously identified a class of small molecule allosteric inhibitors that specifically inhibit the Tyr phosphatase activity of Eya2. Herein, we determined the crystal structure of the Eya2 ED in complex with NCGC00249987 (a representative compound in this class), revealing that it binds to an induced pocket distant from the active site. NCGC00249987 binding leads to a conformational change of the active site that is unfavorable for Mg2+ binding, thereby inhibiting Eya2's Tyr phosphatase activity. We demonstrated, using genetic mutations, that migration, invadopodia formation, and invasion of lung adenocarcinoma cells are dependent on Eya2 Tyr phosphatase activity, whereas growth and survival are not. Further, we demonstrate that NCGC00249987 specifically targets migration, invadopodia formation, and invasion of lung cancer cells, but that it does not inhibit cell growth or survival. The compound has no effect on lung cancer cells carrying an Eya2 F290Y mutant that abolishes compound binding, indicating that NCGC00249987 is on target in lung cancer cells. These data suggest that the NCGC00249987 allosteric inhibitor can be used as a chemical probe to study the function of the Eya2 Tyr phosphatase activity in cells, and may have the potential to be developed into an anti-metastatic agent for cancers reliant on Eya2's Tyr phosphatase activity. Structural and functional analyses of an allosteric Eya2 phosphatase inhibitor that has on target effects in human lung cancer cells.,Anantharajan J, Zhou H, Zhang L, Hotz T, Vincent MY, Blevins MA, Jansson AE, Liang Kuan JW, Ng EY, Yeo K, Baburajendran N, Lin G, Hung AW, Joy J, Patnaik S, Marugan J, Rudra P, Ghosh D, Hill J, Keller TH, Zhao R, Ford HL, Kang C Mol Cancer Ther. 2019 Jul 8. pii: 1535-7163.MCT-18-1239. doi:, 10.1158/1535-7163.MCT-18-1239. PMID:31285279[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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