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Insights Into the Allosteric Inhibition of the SUMO E2 Enzyme Ubc9.

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?mm. Mechanistic and biophysical analyses, coupled with molecular dynamics simulations, point toward ligand-induced rigidification of Ubc9 as a mechanism of inhibition.

SUBMITTER: Hewitt WM

PROVIDER: S-EPMC4973392 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Insights Into the Allosteric Inhibition of the SUMO E2 Enzyme Ubc9.

Hewitt William M WM Lountos George T GT Zlotkowski Katherine K Dahlhauser Samuel D SD Saunders Lindsey B LB Needle Danielle D Tropea Joseph E JE Zhan Chendi C Wei Guanghong G Ma Buyong B Nussinov Ruth R Waugh David S DS Schneekloth John S JS

Angewandte Chemie (International ed. in English) 20160401 19

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 i ...[more]

PMID: 27038327

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