7XV8
Crystal structure of the Human TR4 DNA-Binding Domain Homodimer Bound to DR1 Response Element
Summary for 7XV8
Entry DOI | 10.2210/pdb7xv8/pdb |
Descriptor | Nuclear receptor subfamily 2 group C member 2, DNA (5'-D(*GP*GP*CP*AP*GP*AP*GP*GP*TP*CP*AP*AP*AP*GP*GP*TP*CP*A)-3'), DNA (5'-D(*CP*TP*GP*AP*CP*CP*TP*TP*TP*GP*AP*CP*CP*TP*CP*TP*GP*C)-3'), ... (5 entities in total) |
Functional Keywords | transcriptional regulation, dna binding, protein-dna complex, dna binding protein-dna complex, dna binding protein/dna |
Biological source | Homo sapiens (human) More |
Total number of polymer chains | 4 |
Total formula weight | 29017.62 |
Authors | |
Primary citation | Liu, Y.,Ma, L.,Li, M.,Tian, Z.,Yang, M.,Wu, X.,Wang, X.,Shang, G.,Xie, M.,Chen, Y.,Liu, X.,Jiang, L.,Wu, W.,Xu, C.,Xia, L.,Li, G.,Dai, S.,Chen, Z. Structures of human TR4LBD-JAZF1 and TR4DBD-DNA complexes reveal the molecular basis of transcriptional regulation. Nucleic Acids Res., 51:1443-1457, 2023 Cited by PubMed Abstract: Testicular nuclear receptor 4 (TR4) modulates the transcriptional activation of genes and plays important roles in many diseases. The regulation of TR4 on target genes involves direct interactions with DNA molecules via the DNA-binding domain (DBD) and recruitment of coregulators by the ligand-binding domain (LBD). However, their regulatory mechanisms are unclear. Here, we report high-resolution crystal structures of TR4DBD, TR4DBD-DNA complexes and the TR4LBD-JAZF1 complex. For DNA recognition, multiple factors come into play, and a specific mutual selectivity between TR4 and target genes is found. The coactivators SRC-1 and CREBBP can bind at the interface of TR4 originally occupied by the TR4 activation function region 2 (AF-2); however, JAZF1 suppresses the binding through a novel mechanism. JAZF1 binds to an unidentified surface of TR4 and stabilizes an α13 helix never reported in the nuclear receptor family. Moreover, the cancer-associated mutations affect the interactions and the transcriptional activation of TR4 in vitro and in vivo, respectively. Overall, our results highlight the crucial role of DNA recognition and a novel mechanism of how JAZF1 reinforces the autorepressed conformation and influences the transcriptional activation of TR4, laying out important structural bases for drug design for a variety of diseases, including diabetes and cancers. PubMed: 36651297DOI: 10.1093/nar/gkac1259 PDB entries with the same primary citation |
Experimental method | X-RAY DIFFRACTION (3.199 Å) |
Structure validation
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