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-Structure paper
タイトル | Structural insights into ligand recognition, activation, and signaling of the α adrenergic receptor. |
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ジャーナル・号・ページ | Sci Adv, Vol. 8, Issue 9, Page eabj5347, Year 2022 |
掲載日 | 2022年3月4日 |
著者 | Jun Xu / Sheng Cao / Harald Hübner / Dorothée Weikert / Geng Chen / Qiuyuan Lu / Daopeng Yuan / Peter Gmeiner / Zheng Liu / Yang Du / |
PubMed 要旨 | 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 ...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. |
リンク | Sci Adv / PubMed:35245122 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 3.0 - 3.6 Å |
構造データ | EMDB-31147, PDB-7ej0: EMDB-31156, PDB-7ej8: EMDB-31157, PDB-7eja: EMDB-31162, PDB-7ejk: |
化合物 | ChemComp-E5E: ChemComp-J59: ChemComp-CZX: ChemComp-J5C: |
由来 |
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キーワード | MEMBRANE PROTEIN (膜タンパク質) / alpha2A-adrenergic receptor / signaling complex / cryo-EM (低温電子顕微鏡法) |