9J89

zbp1 nucleic acid complex

Summary for 9J89

• Entry DOI: 10.2210/pdb9j89/pdb
• Descriptor: DNA (5'-D(P*CP*AP*CP*GP*CP*A)-3'), Z-DNA-binding protein 1, RNA (5'-R(P*UP*GP*CP*GP*UP*G)-3'), ... (5 entities in total)
• Functional Keywords: zbp1, dna binding protein/dna/rna, dna binding protein-dna-rna complex
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 8
• Total formula weight: 36257.56

Authors

Gao, A.M.,Zhou, C. (deposition date: 2024-08-20, release date: 2025-06-25)

Primary citation

He, J.,Zhu, Y.,Tian, Z.,Liu, M.,Gao, A.,Fu, W.,Lu, F.,Sun, Y.,Guo, Y.,Pan, R.,Ji, Y.,Chen, J.,Lu, H.,Lin, J.,Liang, X.,Kim, C.,Zhou, C.,Jiao, H.
ZBP1 senses spliceosome stress through Z-RNA:DNA hybrid recognition.
Mol.Cell, 85:1790-1805.e7, 2025

PubMed Abstract: Z-DNA-binding protein 1 (ZBP1; also known as DAI or DLM-1) regulates cell death and inflammation by sensing left-handed double-helical nucleic acids, including Z-RNA and Z-DNA. However, the physiological conditions that generate Z-form nucleic acids (Z-NAs) and activate ZBP1-dependent signaling pathways remain largely elusive. In this study, we developed a probe, Zα-mFc, that specifically detected both Z-DNA and Z-RNA. Utilizing this probe, we discovered that inhibiting spliceosome causes nuclear accumulation of Z-RNA:DNA hybrids, which are sensed by ZBP1 via its Zα domains, triggering apoptosis and necroptosis in mammalian cells. Furthermore, we solved crystal structures of the human or mouse Zα1 domain complexed with a 6-bp RNA:DNA hybrid, revealing that the RNA:DNA hybrid adopts a left-handed conformation. Our findings demonstrate that the spliceosome acts as a checkpoint preventing accumulation of Z-RNA:DNA hybrids, which potentially function as endogenous ligands activating ZBP1-dependent cell death pathways.

PubMed: 40267921
DOI: 10.1016/j.molcel.2025.04.004

Experimental method

X-RAY DIFFRACTION (1.58 Å)