6b5q

DCN1 bound to 38

spinqualitylabelsall models 6b5q, resolution 2.16Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6b5q is a 4 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.16Å Ligands: 1XY, 2KY, CZS, MLY, PGE, PPI Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function DCNL1_HUMAN Part of an E3 ubiquitin ligase complex for neddylation. Required for neddylation of cullin components of E3 cullin-RING ubiquitin ligase complexes by enhancing the rate of cullins neddylation. Functions to recruit the NEDD8-charged E2 enzyme to the cullin component. Involved in the release of inhibitory effets of CAND1 on cullin-RING ligase E3 complex assembly and activity. Acts also as an oncogene facilitating malignant transformation and carcinogenic progression (By similarity). Publication Abstract from PubMed 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 KD 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. High-Affinity Peptidomimetic Inhibitors of the DCN1-UBC12 Protein-Protein Interaction.,Zhou H, Zhou W, Zhou B, Liu L, Chern TR, Chinnaswamy K, Lu J, Bernard D, Yang CY, Li S, Wang M, Stuckey J, Sun Y, Wang S J Med Chem. 2018 Feb 26. doi: 10.1021/acs.jmedchem.7b01455. PMID:29438612 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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