7XV9

Crystal structure of the Human TR4 DNA-Binding Domain

Summary for 7XV9

• Entry DOI: 10.2210/pdb7xv9/pdb
• Descriptor: Nuclear receptor subfamily 2 group C member 2, ZINC ION (3 entities in total)
• Functional Keywords: nuclear receptor, dna binding protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 18637.25

Authors

Liu, Y.,Chen, Z. (deposition date: 2022-05-21, release date: 2022-12-28, Last modification date: 2023-11-29)

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

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: 36651297
DOI: 10.1093/nar/gkac1259

Experimental method

X-RAY DIFFRACTION (1.599 Å)