A Small Molecule That Switches a Ubiquitin Ligase from a Processive to a Distributive Enzymatic Mechanism
Kathman SG, Span I, Smith AT, Xu Z, Zhan J, Rosenzweig AC, Statsyuk AV (2015)
Publication Type: Journal article
Publication year: 2015
Journal
Book Volume: 137
Pages Range: 12442-12445
Journal Issue: 39
DOI: 10.1021/jacs.5b06839
Abstract
E3 ligases are genetically implicated in many human diseases, yet E3 enzyme mechanisms are not fully understood, and there is a strong need for pharmacological probes of E3s. We report the discovery that the HECT E3 Nedd4-1 is a processive enzyme and that disruption of its processivity by biochemical mutations or small molecules switches Nedd4-1 from a processive to a distributive mechanism of polyubiquitin chain synthesis. Furthermore, we discovered and structurally characterized the first covalent inhibitor of Nedd4-1, which switches Nedd4-1 from a processive to a distributive mechanism. To visualize the binding mode of the Nedd4-1 inhibitor, we used X-ray crystallography and solved the first structure of a Nedd4-1 family ligase bound to an inhibitor. Importantly, our study shows that processive Nedd4-1, but not the distributive Nedd4-1:inhibitor complex, is able to synthesize polyubiquitin chains on the substrate in the presence of the deubiquitinating enzyme USP8. Therefore, inhibition of E3 ligase processivity is a viable strategy to design E3 inhibitors. Our study provides fundamental insights into the HECT E3 mechanism and uncovers a novel class of HECT E3 inhibitors.
Authors with CRIS profile
Involved external institutions
United States (USA) (US)How to cite
APA:
Kathman, S.G., Span, I., Smith, A.T., Xu, Z., Zhan, J., Rosenzweig, A.C., & Statsyuk, A.V. (2015). A Small Molecule That Switches a Ubiquitin Ligase from a Processive to a Distributive Enzymatic Mechanism. Journal of the American Chemical Society, 137(39), 12442-12445. https://dx.doi.org/10.1021/jacs.5b06839
MLA:
Kathman, Stefan G., et al. "A Small Molecule That Switches a Ubiquitin Ligase from a Processive to a Distributive Enzymatic Mechanism." Journal of the American Chemical Society 137.39 (2015): 12442-12445.
BibTeX: Download