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Molecular mechanism of a covalent allosteric inhibitor of SUMO E1 activating enzyme

Author

Listed:
  • Zongyang Lv

    (Medical University of South Carolina)

  • Lingmin Yuan

    (Medical University of South Carolina)

  • James H. Atkison

    (Medical University of South Carolina)

  • Katelyn M. Williams

    (Medical University of South Carolina)

  • Ramir Vega

    (Beckman Research Institute of City of Hope)

  • E. Hampton Sessions

    (Sanford Burnham Prebys Medical Discovery Institute at Lake Nona)

  • Daniela B. Divlianska

    (Sanford Burnham Prebys Medical Discovery Institute at Lake Nona)

  • Christopher Davies

    (Medical University of South Carolina)

  • Yuan Chen

    (Beckman Research Institute of City of Hope)

  • Shaun K. Olsen

    (Medical University of South Carolina)

Abstract

E1 enzymes activate ubiquitin (Ub) and ubiquitin-like modifiers (Ubls) in the first step of Ub/Ubl conjugation cascades and represent potential targets for therapeutic intervention in cancer and other life-threatening diseases. Here, we report the crystal structure of the E1 enzyme for the Ubl SUMO in complex with a recently discovered and highly specific covalent allosteric inhibitor (COH000). The structure reveals that COH000 targets a cryptic pocket distinct from the active site that is completely buried in all previous SUMO E1 structures and that COH000 binding to SUMO E1 is accompanied by a network of structural changes that altogether lock the enzyme in a previously unobserved inactive conformation. These structural changes include disassembly of the active site and a 180° rotation of the catalytic cysteine-containing SCCH domain, relative to conformational snapshots of SUMO E1 poised to catalyze adenylation. Altogether, our study provides a molecular basis for the inhibitory mechanism of COH000 and its SUMO E1 specificity, and also establishes a framework for potential development of molecules targeting E1 enzymes for other Ubls at a cryptic allosteric site.

Suggested Citation

  • Zongyang Lv & Lingmin Yuan & James H. Atkison & Katelyn M. Williams & Ramir Vega & E. Hampton Sessions & Daniela B. Divlianska & Christopher Davies & Yuan Chen & Shaun K. Olsen, 2018. "Molecular mechanism of a covalent allosteric inhibitor of SUMO E1 activating enzyme," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-07015-1
    DOI: 10.1038/s41467-018-07015-1
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    Cited by:

    1. Mohammad Afsar & GuanQun Liu & Lijia Jia & Eliza A. Ruben & Digant Nayak & Zuberwasim Sayyad & Priscila dos Santos Bury & Kristin E. Cano & Anindita Nayak & Xiang Ru Zhao & Ankita Shukla & Patrick Sun, 2023. "Cryo-EM structures of Uba7 reveal the molecular basis for ISG15 activation and E1-E2 thioester transfer," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    2. Lingmin Yuan & Fei Gao & Zongyang Lv & Digant Nayak & Anindita Nayak & Priscila dos Santos Bury & Kristin E. Cano & Lijia Jia & Natalia Oleinik & Firdevs Cansu Atilgan & Besim Ogretmen & Katelyn M. Wi, 2022. "Crystal structures reveal catalytic and regulatory mechanisms of the dual-specificity ubiquitin/FAT10 E1 enzyme Uba6," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

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