6B5Q
DCN1 bound to 38
Summary for 6B5Q
| Entry DOI | 10.2210/pdb6b5q/pdb |
| Related PRD ID | PRD_002285 |
| Descriptor | DCN1-like protein 1, Peptidomimetic Inhibitors DI-591, TRIETHYLENE GLYCOL, ... (4 entities in total) |
| Functional Keywords | e3 ligase, complex, ligase-inhibitor complex, ligase, ligase/inhibitor |
| Biological source | Homo sapiens (Human) More |
| Cellular location | Nucleus : Q96GG9 |
| Total number of polymer chains | 4 |
| Total formula weight | 54254.76 |
| Authors | Stuckey, J. (deposition date: 2017-09-29, release date: 2018-02-28, Last modification date: 2023-11-15) |
| Primary citation | Zhou, H.,Zhou, W.,Zhou, B.,Liu, L.,Chern, T.R.,Chinnaswamy, K.,Lu, J.,Bernard, D.,Yang, C.Y.,Li, S.,Wang, M.,Stuckey, J.,Sun, Y.,Wang, S. High-Affinity Peptidomimetic Inhibitors of the DCN1-UBC12 Protein-Protein Interaction. J. Med. Chem., 61:1934-1950, 2018 Cited by PubMed Abstract: The Cullin-RING ligases (CRLs) regulate the turnover of approximately 20% of the proteins in mammalian cells and are emerging therapeutic targets in human diseases. The activation of CRLs requires the neddylation of their cullin subunit, which is controlled by an activation complex consisting of Cullin-RBX1-UBC12-NEDD8-DCN1. Herein, we describe the design, synthesis, and evaluation of peptidomimetics targeting the DCN1-UBC12 protein-protein interaction. Starting from a 12-residue UBC12 peptide, we have successfully obtained a series of peptidomimetic compounds that bind to DCN1 protein with K values of <10 nM. Determination of a cocrystal structure of a potent peptidomimetic inhibitor complexed with DCN1 provides the structural basis for their high-affinity interaction. Cellular investigation of one potent DCN1 inhibitor, compound 36 (DI-404), reveals that it effectively and selectively inhibits the neddylation of cullin 3 over other cullin members. Further optimization of DI-404 may yield a new class of therapeutics for the treatment of human diseases in which cullin 3 CRL plays a key role. PubMed: 29438612DOI: 10.1021/acs.jmedchem.7b01455 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.16 Å) |
Structure validation
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