4RZF
Crystal Structure Analysis of the NUR77 Ligand Binding Domain, S441W mutant
Summary for 4RZF
Entry DOI | 10.2210/pdb4rzf/pdb |
Related | 4RZE 4RZG |
Descriptor | Nuclear receptor subfamily 4 group A member 1, GLYCEROL (3 entities in total) |
Functional Keywords | transcription |
Biological source | Homo sapiens (human) |
Cellular location | Cytoplasm: P22736 |
Total number of polymer chains | 2 |
Total formula weight | 57702.77 |
Authors | |
Primary citation | Li, L.,Liu, Y.,Chen, H.Z.,Li, F.W.,Wu, J.F.,Zhang, H.K.,He, J.P.,Xing, Y.Z.,Chen, Y.,Wang, W.J.,Tian, X.Y.,Li, A.Z.,Zhang, Q.,Huang, P.Q.,Han, J.,Lin, T.,Wu, Q. Impeding the interaction between Nur77 and p38 reduces LPS-induced inflammation. Nat.Chem.Biol., 11:339-346, 2015 Cited by PubMed Abstract: 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-κB activity and suppressing aberrant cytokine production. Nur77 directly associates with p65 to block its binding to the κB element. However, this function of Nur77 is countered by the LPS-activated p38α phosphorylation of Nur77. Dampening the interaction between Nur77 and p38α 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-p38α interaction by targeting the ligand-binding domain of Nur77 and restored the suppression of the hyperinflammatory response through Nur77 inhibition of NF-κB. This study associates the nuclear receptor with immune homeostasis and implicates a new therapeutic strategy to treat hyperinflammatory responses by targeting a p38α substrate to modulate p38α-regulated functions. PubMed: 25822914DOI: 10.1038/nchembio.1788 PDB entries with the same primary citation |
Experimental method | X-RAY DIFFRACTION (1.99 Å) |
Structure validation
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