9nr3

CRBN-DDB1 in complex with GLUL-cN

spinqualitylabelsall models 9nr3, resolution 2.93Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9nr3 is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.93Å Ligands: SNN, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease GLNA_HUMAN Defects in GLUL are the cause of congenital systemic glutamine deficiency (CSGD) [MIM:610015. CSGD is a rare developmental disorder with severe brain malformation resulting in multi-organ failure and neonatal death. Glutamine is largely absent from affected patients serum, urine and cerebrospinal fluid. Function GLNA_HUMAN This enzyme has 2 functions: it catalyzes the production of glutamine and 4-aminobutanoate (gamma-aminobutyric acid, GABA), the latter in a pyridoxal phosphate-independent manner (By similarity). Essential for proliferation of fetal skin fibroblasts. Publication Abstract from PubMed 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. PCMT1 generates the C-terminal cyclic imide degron on CRBN substrates.,Zhao Z, Xu W, Feng EY, Cao S, Hermoso-Lopez A, Pena-Vega P, Lloyd HC, Porter AKD, Guzman M, Zheng N, Woo CM Nat Chem Biol. 2025 Dec 29. doi: 10.1038/s41589-025-02106-9. PMID:41461925 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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