Insights Into the Allosteric Inhibition of the SUMO E2 Enzyme Ubc9.
Angew Chem Int Ed Engl
; 55(19): 5703-7, 2016 05 04.
Article
em En
| MEDLINE
| ID: mdl-27038327
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 1.9-5.8â
mm. Mechanistic and biophysical analyses, coupled with molecular dynamics simulations, point toward ligand-induced rigidification of Ubc9 as a mechanism of inhibition.
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Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Enzimas de Conjugação de Ubiquitina
Limite:
Humans
Idioma:
En
Revista:
Angew Chem Int Ed Engl
Ano de publicação:
2016
Tipo de documento:
Article
País de afiliação:
Estados Unidos