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Crystal structure of MAGE-A11 bound to the PCF11 degron
Structural highlights
FunctionPCF11_HUMAN Component of pre-mRNA cleavage complex II.MAGAB_HUMAN Acts as androgen receptor coregulator that increases androgen receptor activity by modulating the receptors interdomain interaction. May play a role in embryonal development and tumor transformation or aspects of tumor progression.[1] Publication Abstract from PubMedTestis-restricted melanoma antigen (MAGE) proteins are frequently hijacked in cancer and play a critical role in tumorigenesis. MAGEs assemble with E3 ubiquitin ligases and function as substrate adaptors that direct the ubiquitination of novel targets, including key tumor suppressors. However, how MAGEs recognize their targets is unknown and has impeded the development of MAGE-directed therapeutics. Here, we report the structural basis for substrate recognition by MAGE ubiquitin ligases. Biochemical analysis of the degron motif recognized by MAGE-A11 and the crystal structure of MAGE-A11 bound to the PCF11 substrate uncovered a conserved substrate binding cleft (SBC) in MAGEs. Mutation of the SBC disrupted substrate recognition by MAGEs and blocked MAGE-A11 oncogenic activity. A chemical screen for inhibitors of MAGE-A11:substrate interaction identified 4-Aminoquinolines as potent inhibitors of MAGE-A11 that show selective cytotoxicity. These findings provide important insights into the large family of MAGE ubiquitin ligases and identify approaches for developing cancer-specific therapeutics. Structural basis for substrate recognition and chemical inhibition of oncogenic MAGE ubiquitin ligases.,Yang SW, Huang X, Lin W, Min J, Miller DJ, Mayasundari A, Rodrigues P, Griffith EC, Gee CT, Li L, Li W, Lee RE, Rankovic Z, Chen T, Potts PR Nat Commun. 2020 Oct 1;11(1):4931. doi: 10.1038/s41467-020-18708-x. PMID:33004795[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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