Dissecting the Specificity of Adenosyl Sulfamate Inhibitors Targeting the Ubiquitin-Activating Enzyme

Mohit Misra, Maximilian Kuhn, Mark Löbel, Heeseon An, Alexander V. Statsyuk, Christoph Sotriffer, Hermann Schindelin*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

Targeting the activating enzymes (E1) of ubiquitin (Ub) and ubiquitin-like modifiers (Ubls) has emerged as a promising anti-cancer strategy, possibly overcoming the ineffectiveness of proteasome inhibitors against solid tumors. Here, we report crystal structures of the yeast ubiquitin E1 (Uba1) with three adenosyl sulfamate inhibitors exhibiting different E1 specificities, which are all covalently linked to ubiquitin. The structures illustrate how the chemically diverse inhibitors are accommodated within the adenylation active site. When compared with the previously reported structures of various E1 enzymes, our structures provide the basis of the preferences of these inhibitors for different Ub/Ubl-activating enzymes. In vitro inhibition assays and molecular dynamics simulations validated the specificities of the inhibitors as deduced from the structures. Taken together, the structures establish a framework for the development of additional compounds targeting E1 enzymes, which will display higher potency and selectivity. Misra et al. report crystal structures of yeast ubiquitin-activating enzyme (Uba1) in complex with three adenosyl sulfamates covalently linked to ubiquitin. Targeting specific features in the ATP-binding pockets of individual activating (E1) enzymes by rational modulation of the nucleobase extensions of these compounds will yield specific and potent inhibitors.

Original languageEnglish
JournalStructure
DOIs
StateAccepted/In press - Aug 22 2016

Keywords

  • Adenosyl sulfamate inhibitors
  • Cancer
  • Drug design
  • E1 enzymes
  • Ubiquitin
  • Ubiquitin-activating enzyme
  • Ubiquitin-like protein

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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