8THK

Cryo-EM structure of A61603-bound alpha-1A-adrenergic receptor in complex with heterotrimeric Gq-protein

Summary for 8THK

• Entry DOI: 10.2210/pdb8thk/pdb
• EMDB information: 41267
• Descriptor: Guanine nucleotide-binding protein G(i) subunit alpha-2,Guanine nucleotide-binding protein G(s) subunit alpha isoforms short,Guanine nucleotide-binding protein G(q) 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: alpha-1a-adrenergic receptor, a61603, signaling protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 160827.61

Authors

Su, M.,Huang, X.Y. (deposition date: 2023-07-17, release date: 2023-08-16, Last modification date: 2024-11-06)

Primary citation

Su, M.,Wang, J.,Xiang, G.,Do, H.N.,Levitz, J.,Miao, Y.,Huang, X.Y.
Structural basis of agonist specificity of alpha 1A -adrenergic receptor.
Nat Commun, 14:4819-4819, 2023

PubMed Abstract: α-adrenergic receptors (α-ARs) play critical roles in the cardiovascular and nervous systems where they regulate blood pressure, cognition, and metabolism. However, the lack of specific agonists for all α subtypes has limited our understanding of the physiological roles of different α-AR subtypes, and led to the stagnancy in agonist-based drug development for these receptors. Here we report cryo-EM structures of α-AR in complex with heterotrimeric G-proteins and either the endogenous common agonist epinephrine or the α-AR-specific synthetic agonist A61603. These structures provide molecular insights into the mechanisms underlying the discrimination between α-AR and α-AR by A61603. Guided by the structures and corresponding molecular dynamics simulations, we engineer α-AR mutants that are not responsive to A61603, and α-AR mutants that can be potently activated by A61603. Together, these findings advance our understanding of the agonist specificity for α-ARs at the molecular level, opening the possibility of rational design of subtype-specific agonists.

PubMed: 37563160
DOI: 10.1038/s41467-023-40524-2

Experimental method

ELECTRON MICROSCOPY (2.6 Å)