9rpv | pdb_00009rpv

Structure of the ZAK-bound human disome

spinqualitylabelsall models 9rpv, resolution 2.35Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9rpv is a 11 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: Electron Microscopy, Resolution 2.35Å Ligands: 1MA, 4AC, 4SU, 5MC, 6MZ, A2M, ACE, ANM, B8N, G7M, HIC, M3L, MA6, MG, MLZ, OMC, OMG, OMU, PSU, UR3, UY1, V5N, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function EDF1_HUMAN Transcriptional coactivator stimulating NR5A1 and ligand-dependent NR1H3/LXRA and PPARG transcriptional activities. Enhances the DNA-binding activity of ATF1, ATF2, CREB1 and NR5A1. Regulates nitric oxid synthase activity probably by sequestering calmodulin in the cytoplasm. May function in endothelial cells differentiation, hormone-induced cardiomyocytes hypertrophy and lipid metabolism. Publication Abstract from PubMed Ribosome collisions activate the ribotoxic stress response mediated by the MAP3K ZAK, which in turn regulates cell-fate consequences through downstream phosphorylation of the MAPKs p38 and JNK(1). Despite the critical role of ZAK during cellular stress, a mechanistic and structural understanding of ZAK-ribosome interactions and how these lead to activation remain elusive. Here we combine biochemistry and cryo-electron microscopy to discover distinct ZAK-ribosome interactions required for constitutive recruitment and for activation. We find that upon induction of ribosome collisions, interactions between ZAK and the ribosomal protein RACK1 enable its activation by dimerization of its SAM domains at the collision interface. Furthermore, we discover how this process is negatively regulated by the ribosome-binding protein SERBP1 to prevent constitutive ZAK activation. Characterization of novel SAM variants as well as a known pathogenic variant of the SAM domain of ZAK supports a key role of the SAM domain in regulating kinase activity on and off the ribosome, with some mutants bypassing the ribosome requirement for ZAK activation. Collectively, our data provide a mechanistic blueprint of the kinase activity of ZAK at the collided ribosome interface. ZAK activation at the collided ribosome.,Huso VL, Niu S, Catipovic MA, Saba JA, Denk T, Park E, Cheng J, Berninghausen O, Becker T, Green R, Beckmann R Nature. 2025 Nov 19. doi: 10.1038/s41586-025-09772-8. PMID:41261136 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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