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

Yang, Seung Wook; Huang, Xin; Lin, Wenwei; Min, Jaeki; Miller, Darcie J.; Mayasundari, Anand; Rodrigues, Patrick; Griffith, Elizabeth C.; Gee, Clifford T.; Li, Lei; Li, Wei; Lee, Richard E.; Rankovic, Zoran; Chen, Taosheng; Potts, Patrick Ryan

doi:10.1038/s41467-020-18708-x

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

Journal Article · Thu Oct 01 00:00:00 EDT 2020 · Nature Communications

DOI:https://doi.org/10.1038/s41467-020-18708-x· OSTI ID:1671124

Yang, Seung Wook ^[1]; Huang, Xin ^[1]; Lin, Wenwei ^[1]; Min, Jaeki ^[1]; Miller, Darcie J. ^[1]; Mayasundari, Anand ^[1]; Rodrigues, Patrick ^[1]; Griffith, Elizabeth C. ^[1]; Gee, Clifford T. ^[1]; Li, Lei ^[1]; Li, Wei ^[2]; Lee, Richard E. ^[1]; Rankovic, Zoran ^[1]; Chen, Taosheng ^[1]; Potts, Patrick Ryan ^[1]

St. Jude Children’s Research Hospital, Memphis, TN (United States)
Univ. of California, Irvine, CA (United States)

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.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES)

Contributing Organization:: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)

OSTI ID:: 1671124

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 11; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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