Tomographic docking suggests the mechanism of auxin receptor TIR1 selectivity

TL;DR

This paper introduces tomographic docking, a novel computational method that models ligand binding along the depth of the receptor pocket, revealing a three-step mechanism of auxin receptor TIR1 selectivity and aiding herbicide development.

Contribution

The study presents a new tomographic docking approach that captures binding interactions along the pocket depth, providing insights into ligand selectivity mechanisms.

Findings

Selectivity relates to constraints along the ligand's path to the pocket base.

Binding involves a three-step process: niche engagement, molecular filtering, and pocket binding.

Only ligands reaching the pocket base enable co-receptor binding, acting as active auxins.

Abstract

We study the binding of plant hormone IAA on its receptor TIR1 introducing a novel computational method that we call tomographic docking and that accounts for interactions occurring along the depth of the binding pocket. Our results suggest that selectivity is related to constraints that potential ligands encounter on their way from the surface of the protein to their final position at the pocket bottom. Tomographic docking helps develop specific hypotheses about ligand binding, distinguishing binders from non-binders, and suggests that binding is a three-step mechanism, consisting of engagement with a niche in the back wall of the pocket, interaction with a molecular filter which allows or precludes further descent of ligands, and binding on the pocket base. Only molecules that are able to descend the pocket and bind at its base allow the co-receptor IAA7 to bind on the complex, thus behaving as active auxins. Analyzing the interactions at different depths, our new method helps in identifying critical residues that constitute preferred future study targets and in the quest for safe and effective herbicides. Also, it has the potential to extend the utility of docking from ligand searches to the study of processes contributing to selectivity.