Structural basis for substrate recognition and chemical inhibition of oncogenic MAGE ubiquitin ligases

Seung Wook Yang, Xin Huang, Wenwei Lin, Jaeki Min, Darcie J. Miller, Anand Mayasundari, Patrick Rodrigues, Elizabeth C. Griffith, Clifford T. Gee, Lei Li, Wei Li, Richard E. Lee, Zoran Rankovic, Taosheng Chen and Patrick Ryan Potts ()
Additional contact information
Seung Wook Yang: St. Jude Children’s Research Hospital
Xin Huang: St. Jude Children’s Research Hospital
Wenwei Lin: St. Jude Children’s Research Hospital
Jaeki Min: St. Jude Children’s Research Hospital
Darcie J. Miller: St. Jude Children’s Research Hospital
Anand Mayasundari: St. Jude Children’s Research Hospital
Patrick Rodrigues: St. Jude Children’s Research Hospital
Elizabeth C. Griffith: St. Jude Children’s Research Hospital
Clifford T. Gee: St. Jude Children’s Research Hospital
Lei Li: University of California Irvine
Wei Li: University of California Irvine
Richard E. Lee: St. Jude Children’s Research Hospital
Zoran Rankovic: St. Jude Children’s Research Hospital
Taosheng Chen: St. Jude Children’s Research Hospital
Patrick Ryan Potts: St. Jude Children’s Research Hospital

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: Abstract Testis-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.

Date: 2020
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DOI: 10.1038/s41467-020-18708-x

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