6x6c | pdb_00006x6c

Cryo-EM structure of NLRP1-DPP9-VbP complex

spinqualitylabelsall models 6x6c, resolution 2.90Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6x6c is a 4 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 2.9Å Ligands: GK2 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease DPP9_HUMAN Idiopathic pulmonary fibrosis. Function DPP9_HUMAN Dipeptidyl peptidase that cleaves off N-terminal dipeptides from proteins having a Pro or Ala residue at position 2. Publication Abstract from PubMed Nucleotide-binding domain and leucine-rich repeat pyrin-domain containing protein 1 (NLRP1) is an inflammasome sensor that mediates the activation of caspase-1 to induce cytokine maturation and pyroptosis(1-4). Gain-of-function mutations of NLRP1 cause severe inflammatory diseases of the skin(4-6). NLRP1 contains a function-to-find domain that auto-proteolyses into noncovalently associated subdomains(7-9), and proteasomal degradation of the repressive N-terminal fragment of NLRP1 releases its inflammatory C-terminal fragment (NLRP1 CT)(10,11). Cytosolic dipeptidyl peptidases 8 and 9 (hereafter, DPP8/DPP9) both interact with NLRP1, and small-molecule inhibitors of DPP8/DPP9 activate NLRP1 by mechanisms that are currently unclear(10,12-14). Here we report cryo-electron microscopy structures of the human NLRP1-DPP9 complex alone and with Val-boroPro (VbP), an inhibitor of DPP8/DPP9. The structures reveal a ternary complex that comprises DPP9, full-length NLRP1 and the NLRPT CT. The binding of the NLRP1 CT to DPP9 requires full-length NLRP1, which suggests that NLRP1 activation is regulated by the ratio of NLRP1 CT to full-length NLRP1. Activation of the inflammasome by ectopic expression of the NLRP1 CT is consistently rescued by co-expression of autoproteolysis-deficient full-length NLRP1. The N terminus of the NLRP1 CT inserts into the DPP9 active site, and VbP disrupts this interaction. Thus, VbP weakens the NLRP1-DPP9 interaction and accelerates degradation of the N-terminal fragment(10) to induce inflammasome activation. Overall, these data demonstrate that DPP9 quenches low levels of NLRP1 CT and thus serves as a checkpoint for activation of the NLRP1 inflammasome. DPP9 sequesters the C terminus of NLRP1 to repress inflammasome activation.,Hollingsworth LR, Sharif H, Griswold AR, Fontana P, Mintseris J, Dagbay KB, Paulo JA, Gygi SP, Bachovchin DA, Wu H Nature. 2021 Apr;592(7856):778-783. doi: 10.1038/s41586-021-03350-4. Epub 2021 , Mar 17. PMID:33731932 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Dipeptidyl peptidase 3D structures Pyrin domain

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