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

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

Research output: Contribution to journalArticlepeer-review

44 Scopus citations


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.

Original languageEnglish (US)
Article number5145
JournalNature communications
Issue number1
StatePublished - Dec 1 2018
Externally publishedYes

ASJC Scopus subject areas

  • General Physics and Astronomy
  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology


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