The Arabidopsis thaliana S-domain receptor kinase LORE senses bacterial medium-chain 3-hydroxy fatty acids (mc-3-OH-FAs) as microbe-associated molecular patterns to activate pattern-triggered immunity. How LORE recognises these fatty acid ligands at the molecular level remains unknown. Here, we combined protein structure prediction, protein-ligand interaction modelling and molecular dynamics (MD) simulations with ligand-binding assays using chimeric and mutant receptor ectodomains, and functional analysis of receptor activation to characterise the mc-3-OH-FA binding mechanism. Domain-swap experiments between LORE and its non-binding paralog AtSD1-23 identify the lectin 2 (L2) domain as the ligand-binding domain. Mutational analysis and reverse engineering confirm a hydrophobic pocket in the L2 core as the primary ligand-binding site. Multiple walker Supervised MD (mwSuMD) simulations reveal that the acyl tail enters the pocket first, whilst polar interactions between the headgroup and a flexible L2 loop guide and stabilise the bound state. In support of this model, 3-OH-C10:0 analogues with bulky headgroup modifications dock into the pocket but act as antagonists, presumably by preventing the loop from adopting the conformation required for signalling. Together, these data suggest that the flexible L2 loop has multiple functions: it acts as a dynamic gate regulating pocket access, provides essential anchoring points once the ligand is bound, and contributes to receptor activation. These findings provide a mechanistic framework for immunogenic mc-3-OH-FA sensing by LORE.
Shu, L.-J., Nicoli, A., Yu, F.-Y., Thiry, O. O. A., Deslandes-Herold, G., Luethi, T., Di Pizio, A., Ranf, S.
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