Insights into the Allosteric Inhibition of the SUMO E2 Enzyme Ubc9

William M. Hewitt, George T. Lountos, Katherine Zlotkowski, Samuel D. Dahlhauser, Lindsey B. Saunders, Danielle Needle, Joseph E. Tropea, Chendi Zhan, Guanghong Wei, Buyong Ma, Ruth Nussinov, David S. Waugh, John S. Schneekloth*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Conjugation of the small ubiquitin-like modifier (SUMO) to protein substrates is an important disease-associated posttranslational modification, although few inhibitors of this process are known. Herein, we report the discovery of an allosteric small-molecule binding site on Ubc9, the sole SUMO E2 enzyme. An X-ray crystallographic screen was used to identify two distinct small-molecule fragments that bind to Ubc9 at a site distal to its catalytic cysteine. These fragments and related compounds inhibit SUMO conjugation in biochemical assays with potencies of 1.9-5.8 mm. Mechanistic and biophysical analyses, coupled with molecular dynamics simulations, point toward ligand-induced rigidification of Ubc9 as a mechanism of inhibition.

Original languageEnglish
Pages (from-to)5703-5707
Number of pages5
JournalAngewandte Chemie - International Edition
Issue number19
StatePublished - 4 May 2016


  • SUMOylation
  • Ubc9
  • X-ray crystallography
  • allostery
  • inhibitors


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