Trace amine-associated receptors (TAARs) are class A GPCRs that span two distinct physiological roles: TAAR1 is a CNS drug target, whereas TAAR2 to TAAR9 detect volatile amines in the olfactory epithelium. Recent experimental structures resolve their architecture and ligand-binding mode, but capture only static snapshots, which cannot address how the binding site and the overall pocketome respond to ligand binding. Here, we present a simulation library comprising 26 experimental structures of four human and murine genes in the apo and holo states, each in triplicate (total aggregate time of 156 microseconds). Cavities were detected and analysed across the entire receptor surface throughout each trajectory. Orthosteric changes did not follow a single direction when comparing the states: apo sites were neither uniformly smaller nor uniformly more flexible than their holo counterparts, instead pointing to a receptor- specific ligand-receptor interplay that propagates beyond the orthosteric pocket. This plasticity is further highlighted by the size composition and stability of allosteric pockets, which proves that some regions are larger in the apo state while others are larger when a ligand is present. Resolving such trends required pockets to be comparable across trajectories, which a novel global identifier (GID) provides. Although agnostic to functional annotation, the GID recovered the orthosteric site as a single region in both states and matched pockets across replicates of the same receptor-state pair. The result is a dynamic pocketome map of the TAAR family obtained by an approach transferable to other membrane proteins.
Rienaecker, C., Nicoli, A., Selent, J., Di Pizio, A.
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