Dynamic Pocketome of Trace Amine-Associated Receptors

Trace amine-associated receptors (TAARs) serve two primary functions: TAAR1 acts as a CNS drug target, while TAAR2 to TAAR9 identify volatile amines in the olfactory epithelium. Previous experimental structures provided insights into their architecture and ligand-binding mode, yet these static snapshots did not reveal how the binding site and pocketome evolve upon ligand binding.

To address this, researchers compiled a simulation library consisting of 26 experimental structures of four human and murine TAAR genes in both apo and holo states, replicated three times each, amounting to a total simulation time of 156 microseconds.

The team analyzed cavities across the entire receptor surface during each trajectory and observed that orthosteric changes did not consistently follow a single direction when comparing the apo and holo states. Instead, they found that apo sites were neither uniformly smaller nor more flexible than their holo counterparts. This suggests a receptor-specific ligand-receptor interplay that extends beyond the orthosteric pocket, demonstrating the plasticity of the TAAR family.

The researchers also noted significant differences in the size composition and stability of allosteric pockets, indicating that some regions are larger in the apo state while others expand upon ligand binding. To make meaningful comparisons across trajectories, they introduced a novel global identifier (GID) to normalize the pocketome data.

While the GID does not account for functional annotation, it successfully identified the orthosteric site as a single region in both states and correlated pocket features across replicates of the same receptor-state pair. The outcome is a dynamic pocketome map of the TAAR family, generated using a method applicable to other membrane proteins.