8HCG

Crystal structure of mTREX1-dAMP complex

Summary for 8HCG

• Entry DOI: 10.2210/pdb8hcg/pdb
• Related: 8HCC 8HCD 8HCE 8HCF
• Descriptor: Three-prime repair exonuclease 1, PENTAETHYLENE GLYCOL, SODIUM ION, ... (6 entities in total)
• Functional Keywords: trex1, deddh exonuclease, dnase, rnase, damp, hydrolase
• Biological source: Mus musculus (house mouse)
• Total number of polymer chains: 1
• Total formula weight: 27487.58

Authors

Hsiao, Y.Y.,Huang, K.W.,Wu, C.Y. (deposition date: 2022-11-01, release date: 2023-11-08, Last modification date: 2023-12-13)

Primary citation

Huang, K.W.,Wu, C.Y.,Toh, S.I.,Liu, T.C.,Tu, C.I.,Lin, Y.H.,Cheng, A.J.,Kao, Y.T.,Chu, J.W.,Hsiao, Y.Y.
Molecular insight into the specific enzymatic properties of TREX1 revealing the diverse functions in processing RNA and DNA/RNA hybrids.
Nucleic Acids Res., 51:11927-11940, 2023

PubMed Abstract: In various autoimmune diseases, dysfunctional TREX1 (Three prime Repair Exonuclease 1) leads to accumulation of endogenous single-stranded DNA (ssDNA), double-stranded DNA (dsDNA) and DNA/RNA hybrids in the cytoplasm and triggers immune activation through the cGAS-STING pathway. Although inhibition of TREX1 could be a useful strategy for cancer immunotherapy, profiling cellular functions in terms of its potential substrates is a key step. Particularly important is the functionality of processing DNA/RNA hybrids and RNA substrates. The exonuclease activity measurements conducted here establish that TREX1 can digest both ssRNA and DNA/RNA hybrids but not dsRNA. The newly solved structures of TREX1-RNA product and TREX1-nucleotide complexes show that 2'-OH does not impose steric hindrance or specific interactions for the recognition of RNA. Through all-atom molecular dynamics simulations, we illustrate that the 2'-OH-mediated intra-chain hydrogen bonding in RNA would affect the binding with TREX1 and thereby reduce the exonuclease activity. This notion of higher conformational rigidity in RNA leading TREX1 to exhibit weaker catalytic cleavage is further validated by the binding affinity measurements with various synthetic DNA-RNA junctions. The results of this work thus provide new insights into the mechanism by which TREX1 processes RNA and DNA/RNA hybrids and contribute to the molecular-level understanding of the complex cellular functions of TREX1 as an exonuclease.

PubMed: 37870446
DOI: 10.1093/nar/gkad910

Experimental method

X-RAY DIFFRACTION (1.799 Å)