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Ligand-dependent conformational dynamics of the α2A-adrenergic receptor

ABSTRACT: Biased agonists targeting the α2A-adrenergic receptor (α2AAR) have therapeutic potential by preferentially engaging G protein signaling over β-arrestin pathways. Here, we used hydrogen-deuterium exchange mass spectrometry (HDX-MS) to compare α2AAR conformational dynamics across apo, agonist-bound, and GoA-coupled states. We analyzed HDX-MS changes induced by norepinephrine (NorEpi), the endogenous full agonist; dexmedetomidine (Dex), a clinically used full agonist that activates both Gi/o and β-arrestin signaling; and PS75, a Gi/o-biased partial agonist. By quantifying ligand-dependent differences in deuterium uptake and local dynamics, we aimed to define ligand-specific conformational ensembles. These findings provide mechanistic insight into partial agonism and suggest potential implications for biased signaling.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Donghoon Ahn

LAB HEAD: Ka Young

PROVIDER: PXD067629 | Pride | 2026-02-25

REPOSITORIES: Pride

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			Action	DRS
	a2A_ApoDexPS.raw.zip	Raw
	a2A_ApoDexPS_PeptideIdentification.zip	Other
	a2A_ApoNorepi_PeptideIdentification_Set1_2.zip	Other
	a2A_ApoNorepi_PeptideIdentification_Set3.zip	Other
	a2A_ApoNorepi_Set1_2.raw.zip	Raw

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