7EJK

Structure of the alpha2A-adrenergic receptor GoA signaling complex bound to oxymetazoline

Summary for 7EJK

• Entry DOI: 10.2210/pdb7ejk/pdb
• Related: 7EJ8 7EJA 7EL0
• EMDB information: 31162
• Descriptor: Guanine nucleotide-binding protein G(o) subunit alpha, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (6 entities in total)
• Functional Keywords: alpha2a-adrenergic receptor, signaling complex, cryo-em, membrane protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 5
• Total formula weight: 170228.23

Authors

Xu, J.,Cao, S.,Liu, Z.,Du, Y. (deposition date: 2021-04-02, release date: 2022-04-13, Last modification date: 2024-10-23)

Primary citation

Xu, J.,Cao, S.,Hubner, H.,Weikert, D.,Chen, G.,Lu, Q.,Yuan, D.,Gmeiner, P.,Liu, Z.,Du, Y.
Structural insights into ligand recognition, activation, and signaling of the alpha 2A adrenergic receptor.
Sci Adv, 8:eabj5347-eabj5347, 2022

PubMed Abstract: The α adrenergic receptor (αAR) is a G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor that mediates important physiological functions in response to the endogenous neurotransmitters norepinephrine and epinephrine, as well as numerous chemically distinct drugs. However, the molecular mechanisms of drug actions remain poorly understood. Here, we report the cryo-electron microscopy structures of the human αAR-GoA complex bound to norepinephrine and three imidazoline derivatives (brimonidine, dexmedetomidine, and oxymetazoline). Together with mutagenesis and functional data, these structures provide important insights into the molecular basis of ligand recognition, activation, and signaling at the αAR. Further structural analyses uncover different molecular determinants between αAR and βARs for recognition of norepinephrine and key regions that determine the G protein coupling selectivity. Overall, our studies provide a framework for understanding the signal transduction of the adrenergic system at the atomic level, which will facilitate rational structure-based discovery of safer and more effective medications for αAR.

PubMed: 35245122
DOI: 10.1126/sciadv.abj5347

Experimental method

ELECTRON MICROSCOPY (3.4 Å)