Role of substrate recognition in modulating strigolactone receptor selectivity in witchweed

Witchweed, or Striga hermonthica, is a parasitic weed that destroys billions of dollars' worth of crops globally every year. Its germination is stimulated by strigolactones exuded by its host plants. Despite high sequence, structure, and ligand-binding site conservation across different plant species, one strigolactone receptor in witchweed, ShHTL7, uniquely ex-hibits a picomolar EC50 for downstream signaling. Previous biochemical and structural analyses have hypothesized that this unique ligand sensitivity can be attributed to a large binding pocket volume in ShHTL7 resulting in enhanced ability to bind substrates, but additional structural details of the substrate-binding process would help explain its role in modulating the ligand selectivity. Using long-timescale mo-lecular dynamics simulations, we demonstrate that mutations at the entrance of the binding pocket facilitate a more direct ligand-binding pathway to ShHTL7, whereas hydrophobicity at the binding pocket entrance results in a stable anchored state. We also demonstrate that several residues on the D-loop of AtD14 stabilize catalytically inactive conformations. Finally, we show that strigolactone selectivity is not modulated by binding pocket volume. Our results indicate that while ligand binding is not the sole modulator of strigolactone receptor selectivity, it is a significant contributing factor. These results can be used to inform the design of selective antagonists for strigolactone receptors in witchweed.

Automated summary

Witchweed is a parasitic weed that destroys crops globally each year, with its germination stimulated by strigolactones from host plants. The unique sensitivity of the strigolactone receptor ShHTL7 in witchweed has been hypothesized to be due to a large binding pocket volume enhancing substrate binding ability, as shown in biochemical and structural analyses.