Atomistic Mechanism Underlying the Regulation of the GPA1 G Protein Signaling Pathway Mediated by the Gibberellin A1 Phytohormone Binding to the GCR1 Plant G-Protein-Coupled Receptor

We propose an atomistic mechanism suggesting that fundamental plant processes, including seed germination, root elongation, and flower and fruit production, may be regulated by phytohormones such as Gibberellin A1 (GA1) binding to the GCR1 plant G-protein-coupled receptor. This parallels the central roles of GPCRs in animals for vision, taste, smell, pain, depression, and nerve signaling, among others. Validating GCR1 as a genuine GPCR in plants, particularly its interaction with GPA1, G-protein, would mark a groundbreaking advancement in understanding plant processes, both biologically and agronomically. However, experimental confirmation of this interaction and evidence supporting the idea that binding of GA1 to GCR1 would regulate GPA1 activation are lacking. Indeed, the design of experiments to explore these hypotheses is impeded by the absence of structural information relating to interactions of GPA1 with the GA1-GCR1 complex. To address this gap, we employ molecular dynamics and metadynamics simulations to demonstrate that binding GPA1 to the GA1-GCR1 complex induces conformational changes that open up the Ras and Helical domains of GPA1 to release GDP for exchange with GTP, thereby enabling signaling. Our results suggest numerous mutations involving GA1 binding at the GCR1 site and the coupling of GCR1 to the GPA1 G-protein that could be used to validate (or not validate) our predicted mechanism. Such validation would serve as a foundation for devising strategies to design novel agonists and inverse agonists to provide precise control of crucial plant processes.