4rze

Crystal Structure Analysis of the NUR77 Ligand Binding Domain, L437W,D594E mutant

spinqualitylabelsall models 4rze, resolution 2.49Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4rze is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: GOL Related: 4rzf, 4rzg Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [NR4A1_HUMAN] Orphan nuclear receptor. May act concomitantly with NURR1 in regulating the expression of delayed-early genes during liver regeneration. Binds the NGFI-B response element (NBRE) 5'-AAAAGGTCA-3' (By similarity). May inhibit NF-kappa-B transactivation of IL2. Publication Abstract from PubMed Sepsis, a hyperinflammatory response that can result in multiple organ dysfunctions, is a leading cause of mortality from infection. Here, we show that orphan nuclear receptor Nur77 (also known as TR3) can enhance resistance to lipopolysaccharide (LPS)-induced sepsis in mice by inhibiting NF-kappaB activity and suppressing aberrant cytokine production. Nur77 directly associates with p65 to block its binding to the kappaB element. However, this function of Nur77 is countered by the LPS-activated p38alpha phosphorylation of Nur77. Dampening the interaction between Nur77 and p38alpha would favor Nur77 suppression of the hyperinflammatory response. A compound, n-pentyl 2-[3,5-dihydroxy-2-(1-nonanoyl) phenyl]acetate, screened from a Nur77-biased library, blocked the Nur77-p38alpha interaction by targeting the ligand-binding domain of Nur77 and restored the suppression of the hyperinflammatory response through Nur77 inhibition of NF-kappaB. This study associates the nuclear receptor with immune homeostasis and implicates a new therapeutic strategy to treat hyperinflammatory responses by targeting a p38alpha substrate to modulate p38alpha-regulated functions. Impeding the interaction between Nur77 and p38 reduces LPS-induced inflammation.,Li L, Liu Y, Chen HZ, Li FW, Wu JF, Zhang HK, He JP, Xing YZ, Chen Y, Wang WJ, Tian XY, Li AZ, Zhang Q, Huang PQ, Han J, Lin T, Wu Q Nat Chem Biol. 2015 May;11(5):339-46. doi: 10.1038/nchembio.1788. Epub 2015 Mar, 30. PMID:25822914 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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