8VK8

Structure of UbV.d2.1 in complex with Ube2d2

Summary for 8VK8

• Entry DOI: 10.2210/pdb8vk8/pdb
• Descriptor: Ubiquitin-conjugating enzyme E2 D2, Ubiquitin variant D2.1 (2 entities in total)
• Functional Keywords: ubiquitin conjugating enzyme, ubiquitin variant, e2 enzyme, inhibitor, transferase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 8
• Total formula weight: 103228.50

Authors

Middleton, A.J. (deposition date: 2024-01-08, release date: 2024-09-25, Last modification date: 2024-12-18)

Primary citation

McAlpine, J.M.R.B.,Zhu, J.,Pudjihartono, N.,Teyra, J.,Currie, M.J.,Tillett, Z.D.,Dobson, R.C.J.,Sidhu, S.S.,Day, C.L.,Middleton, A.J.
Structural and biophysical characterisation of ubiquitin variants that inhibit the ubiquitin conjugating enzyme Ube2d2.
Febs J., 291:5305-5321, 2024

PubMed Abstract: The ubiquitin-conjugating E2 enzymes play a central role in ubiquitin transfer. Disruptions to the ubiquitin system are implicated in multiple diseases, and as a result, molecules that modulate the activity of the ubiquitin system are of interest. E2 enzyme function relies on interactions with partner proteins, and the disruption of these is an effective way to modulate activity. Here, we report the discovery of ubiquitin variants (UbVs) that inhibit the E2 enzyme, Ube2d2 (UbcH5b). The six UbVs identified inhibit ubiquitin chain building, and the structural and biophysical characterisation of two of these demonstrate they bind to Ube2d2 with low micromolar affinity and high specificity. Both characterised UbVs bind at a site that overlaps with E1 binding, while the more inhibitory UbV has an additional binding site that blocks a critical non-covalent ubiquitin-binding site on the E2 enzyme. The discovery of novel protein-based ubiquitin derivatives that inhibit protein-protein interactions is an important step towards discovering small molecules that inhibit the activity of E2 enzymes. Furthermore, the specificity of the UbVs within the Ube2d family suggests that it may be possible to develop tools to selectively inhibit highly related E2 enzymes.

PubMed: 39473070
DOI: 10.1111/febs.17311

Experimental method

X-RAY DIFFRACTION (2.99 Å)