9H9T
Crystal structure of NEDD4 HECT domain in complex with covalent inhibitor
This is a non-PDB format compatible entry.
Summary for 9H9T
| Entry DOI | 10.2210/pdb9h9t/pdb |
| Related | 9H9O |
| Descriptor | Isoform 4 of E3 ubiquitin-protein ligase NEDD4, ethyl 4-[4-(2-chloranyl-5,6-dihydrobenzo[b][1]benzazepin-11-yl)butylamino]butanoate (3 entities in total) |
| Functional Keywords | covalent ihibitor, complex, ubiquitin, ligase, e3 |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 45154.00 |
| Authors | Cecatiello, V.,Maspero, E.,Polo, S.,Pasqualato, S. (deposition date: 2024-10-31, release date: 2025-06-04) |
| Primary citation | Maspero, E.,Cappa, A.,Weber, J.,Trifiro, P.,Amici, R.,Bruno, A.,Faga, G.,Cecatiello, V.,Fattori, R.,Leuzzi, B.,Taibi, V.,Meroni, G.,Pasi, M.,Romussi, A.,Sartori, L.,Villa, M.,Vultaggio, S.,Ciro, M.,Soffientini, P.,Lombardo, L.,Dahe, S.,Bachi, A.,Varasi, M.,Rossi, M.,Pasqualato, S.,Mercurio, C.,Polo, S. Structure-based design of potent and selective inhibitors of the HECT ligase NEDD4. Commun Chem, 8:164-164, 2025 Cited by PubMed Abstract: Among the human E3 ubiquitin ligases, NEDD4 (Neural precursor cell expressed developmentally down-regulated 4) plays a critical role in development and cancer, making it a compelling therapeutic target. However, no specific NEDD4 inhibitors have advanced in drug development. In this study, we reveal the inhibitory mechanism of Norclomipramine, a tricyclic antidepressant, which inhibits NEDD4-mediated ubiquitin chain elongation by binding to a hydrophobic pocket in the Ub exosite of the N-lobe. Building on this mechanism, we conducted a focused medicinal chemistry campaign, resulting in the development of covalent inhibitors that specifically target the non-catalytic cysteine C627. These compounds exhibit selective binding to NEDD4 over other family members, effectively inhibiting NEDD4-mediated polyubiquitination while leaving monoubiquitinated substrates unaffected. Among these, compound 32 emerged as a potent lead (IC = 0.12 µM) with favorable pharmacokinetic properties, including oral bioavailability, paving the way for future in vivo efficacy studies. PubMed: 40437006DOI: 10.1038/s42004-025-01557-4 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.17 Å) |
Structure validation
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