Authors
Gromak, D., Shaytan, A. K., Herbert, A., Poptsova, M.
Abstract
The p150 isoform of the double-stranded RNA editing enzyme ADAR1 binds Z-DNA and Z-RNA through the conserved winged helix-turn-helix Z domain. Here, we describe an inverse computational design strategy to map protein interactors of Z. We used RFdiffusion and ProteinMPNN to generate around 10,000 synthetic binders optimized for the Z recognition surface, then used their sequences as structural templates for BLASTp searches against the human proteome. Multi-stage screening of around 1,200 candidate regions from 298 proteins via ColabFold pDockQ identified 79 candidates for high-resolution AlphaFold3 modeling, which revealed the m6A reader YTHDC1 as the top-ranked interactor. AlphaFold3 predicts that a glutamate-rich poly-E disordered region of YTHDC1 (residues 199-254) docks into the basic recognition pocket of Z through a charge-complementary mechanism that mimics the phosphate backbone of Z-RNA. Microsecond molecular dynamics simulations confirmed stability of the binary ADAR1p150-YTHDC1 complex, with the Z-poly-E interface maintaining RMSD below 3 Angstrem throughout. Ternary complex simulations showed that dsRNA acts as a co-anchoring scaffold stabilizing simultaneous engagement of both proteins in a catalytically dormant conformation. YTHDC1 localizes to transcription-associated YT bodies where nascent RNAs undergo m6A modification and negative supercoiling promotes Z-DNA formation, suggesting that YTHDC1 recruits ADAR1p150 to promote editing of intron-containing substrates prior to splicing.
Preprint server:
bioRxiv
The authors list and abstract were imported from bioRxiv on 14 Jul 2026.
Advertisement
Stats
- Recommendations n/a n/a positive of 0 vote(s)
- Views 7
- Comments 0