5C91

NEDD4 HECT with covalently bound indole-based inhibitor

Summary for 5C91

• Entry DOI: 10.2210/pdb5c91/pdb
• Related: 2XBB 2XBF
• Descriptor: E3 ubiquitin-protein ligase NEDD4, methyl (2E)-4-{[(5-methoxy-1,2-dimethyl-1H-indol-3-yl)carbonyl]amino}but-2-enoate (3 entities in total)
• Functional Keywords: nedd4, hect, ligase, inhibitor, ligase-ligase inhibitor complex, ligase/ligase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm : P46934
• Total number of polymer chains: 1
• Total formula weight: 45055.38

Authors

Span, I.,Smith, A.T.,Kathman, S.,Statsyuk, A.V.,Rosenzweig, A.C. (deposition date: 2015-06-26, release date: 2015-09-30, Last modification date: 2024-10-09)

Primary citation

Kathman, S.G.,Span, I.,Smith, A.T.,Xu, Z.,Zhan, J.,Rosenzweig, A.C.,Statsyuk, A.V.
A Small Molecule That Switches a Ubiquitin Ligase From a Processive to a Distributive Enzymatic Mechanism.
J. Am. Chem. Soc., 137:12442-12445, 2015

PubMed 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.

PubMed: 26371805
DOI: 10.1021/jacs.5b06839

Experimental method

X-RAY DIFFRACTION (2.44 Å)