29LQ

PanDDA analysis - Crystal structure of the Ubiquitin conjugating enzyme 4 from Leishmania major (LmUbC4) in complex with Z1639162606

Summary for 29LQ

• Entry DOI: 10.2210/pdb29lq/pdb
• Descriptor: Ubiquitin-conjugating enzyme E2 H, 2-fluoro-N,3-dimethylbenzene-1-sulfonamide, CHLORIDE ION, ... (5 entities in total)
• Functional Keywords: ubiquitin conjugating enzyme, ligase
• Biological source: Leishmania major
• Total number of polymer chains: 2
• Total formula weight: 38805.42

Authors

Exertier, C.,Fiorillo, A.,Ilari, A. (deposition date: 2026-03-20, release date: 2026-09-23, Last modification date: 2026-10-07)

Primary citation

Exertier, C.,Antonelli, L.,Liuzzi, A.,Ruffa, M.,Brufani, V.,Colotti, G.,Fiorillo, A.,Ilari, A.
UbC4 from Leishmania is a Druggable E2 Ubiquitin Conjugating Enzyme: Structural Basis and Fragment Hits for Future E2-Recruiting PROTAC Development.
Acs Omega, 11:55759-55771, 2026

PubMed Abstract: Leishmaniasis is a neglected disease that affects around two million people every year. Current treatments are often highly toxic or prone to resistance, underscoring the urgent need for new therapeutic strategies. PROTACs may offer a promising alternative, as they can potentially mitigate both toxicity and resistance. However, very little is known about the ubiquitin-proteasome system (UPS) in . Notably, only two E3 ligases containing a CULT domain have been identified so far, and none carrying a von Hippel-Lindau (VHL) domainthe classical E3 ligase used by clinically advanced PROTACs. In this work, we take an important step toward understanding the UPS in , and we propose that in this organism the UbC4 E2 enzyme, rather than an E3, may be directly exploited to develop a PROTAC able to engage a protein of interest. Here, we report the biochemical and structural characterization of the ubiquitin-conjugating enzyme 4 (UbC4). Through a fragment screening campaign, we identified 10 fragments binding to distinct cavities on UbC4. Among these, five interact with the same noncatalytic pocket that is poorly conserved in humans, while one fragment binds near the catalytic cysteine. Using DeepFrag predictions and molecular docking, we explored fragment elongation strategies to enhance affinity for their respective binding sites, with the goal of guiding the development of E2-recruiting PROTACs or UPS inhibitors for the treatment of leishmaniasis.

PubMed: 42799427
DOI: 10.1021/acsomega.6c05158

Experimental method

X-RAY DIFFRACTION (2.001 Å)