6P5W
Structure of DCN1 bound to 3-methyl-N-((4S,5S)-3-methyl-6-oxo-1-phenyl-4-(p-tolyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridin-5-yl)benzamide
Summary for 6P5W
| Entry DOI | 10.2210/pdb6p5w/pdb |
| Descriptor | Lysozyme,DCN1-like protein 1 chimera, 3-methyl-N-[(4S,5S)-3-methyl-4-(4-methylphenyl)-6-oxo-1-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridin-5-yl]benzamide (3 entities in total) |
| Functional Keywords | e3 ligase, hydrolase, ligase |
| Biological source | Enterobacteria phage T4 More |
| Total number of polymer chains | 1 |
| Total formula weight | 44757.88 |
| Authors | Guy, R.K.,Kim, H.S.,Hammill, J.T.,Scott, D.C.,Schulman, B.A. (deposition date: 2019-05-31, release date: 2019-09-11, Last modification date: 2023-10-11) |
| Primary citation | Kim, H.S.,Hammill, J.T.,Scott, D.C.,Chen, Y.,Min, J.,Rector, J.,Singh, B.,Schulman, B.A.,Guy, R.K. Discovery of Novel Pyrazolo-pyridone DCN1 Inhibitors Controlling Cullin Neddylation. J.Med.Chem., 62:8429-8442, 2019 Cited by PubMed Abstract: Chemical control of cullin neddylation is attracting increased attention based largely on the successes of the NEDD8-activating enzyme (E1) inhibitor pevonedistat. Recently reported chemical probes enable selective and time-dependent inhibition of downstream members of the neddylation trienzymatic cascade including the co-E3, DCN1. In this work, we report the optimization of a novel class of small molecule inhibitors of the DCN1-UBE2M interaction. Rational X-ray co-structure enabled optimization afforded a 25-fold improvement in potency relative to the initial screening hit. The potency gains are largely attributed to additional hydrophobic interactions mimicking the N-terminal acetyl group that drives binding of UBE2M to DCN1. The compounds inhibit the protein-protein interaction, block NEDD8 transfer in biochemical assays, engage DCN1 in cells, and selectively reduce the steady-state neddylation of Cul1 and Cul3 in two squamous carcinoma cell lines harboring DCN1 amplification. PubMed: 31465221DOI: 10.1021/acs.jmedchem.9b00410 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.69 Å) |
Structure validation
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