9NR3
CRBN-DDB1 in complex with GLUL-cN
Summary for 9NR3
| Entry DOI | 10.2210/pdb9nr3/pdb |
| Descriptor | DNA damage-binding protein 1, Protein cereblon, GLUL-cN, ... (4 entities in total) |
| Functional Keywords | ubiquitin ligase, native substrate, degron, glutamine synthetase, crbn, ligase |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 3 |
| Total formula weight | 139413.50 |
| Authors | |
| Primary citation | Zhao, Z.,Xu, W.,Feng, E.Y.,Cao, S.,Hermoso-Lopez, A.,Pena-Vega, P.,Lloyd, H.C.,Porter, A.K.D.,Guzman, M.,Zheng, N.,Woo, C.M. PCMT1 generates the C-terminal cyclic imide degron on CRBN substrates. Nat.Chem.Biol., 2025 Cited by PubMed Abstract: The E3 ligase substrate adapter cereblon (CRBN), the primary target of clinical agents thalidomide and lenalidomide, recognizes endogenous substrates bearing the C-terminal cyclic imide modification. Although C-terminal cyclic imides can form spontaneously, an enzyme that regulates their formation and thereby promotes a biological pathway connecting substrates to CRBN is unknown. Here we report that protein carboxymethyltransferase (PCMT1) promotes formation of C-terminal cyclic imides on C-terminal asparagine residues of CRBN substrates. PCMT1 and CRBN coregulate the levels of metabolic enzymes including glutamine synthetase and inorganic pyrophosphatase 1 in vitro, in cells and in vivo, and this regulation is associated with the proepileptic phenotype of CRBN knockout mouse models. The discovery of an enzyme that regulates CRBN substrates through the C-terminal cyclic imide reveals a previously unknown biological pathway that is perturbed by thalidomide derivatives and provides a biochemical basis for the connection between multiple biological processes and CRBN. PubMed: 41461925DOI: 10.1038/s41589-025-02106-9 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.93 Å) |
Structure validation
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