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- Title
Insights Into the Allosteric Inhibition of the SUMO E2 Enzyme Ubc9.
- Authors
Hewitt, William M.; Lountos, George T.; Zlotkowski, Katherine; Dahlhauser, Samuel D.; Saunders, Lindsey B.; Needle, Danielle; Tropea, Joseph E.; Zhan, Chendi; Wei, Guanghong; Ma, Buyong; Nussinov, Ruth; Waugh, David S.; Schneekloth, John S.
- Abstract
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 m m. Mechanistic and biophysical analyses, coupled with molecular dynamics simulations, point toward ligand-induced rigidification of Ubc9 as a mechanism of inhibition.
- Subjects
ENZYMES; UBIQUITIN; BIOCHEMICAL substrates; CYSTEINE; MOLECULAR dynamics
- Publication
Angewandte Chemie, 2016, Vol 128, Issue 19, p5797
- ISSN
0044-8249
- Publication type
Article
- DOI
10.1002/ange.201511351