6k42 | pdb_00006k42
cryo-EM structure of alpha2BAR-Gi1 complex
Structural highlights
Function[GBG2_HUMAN] Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction (By similarity). [GBB1_MOUSE] Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction (By similarity). [GNAI1_BOVIN] Guanine nucleotide-binding proteins (G proteins) function as transducers downstream of G protein-coupled receptors (GPCRs) in numerous signaling cascades. The alpha chain contains the guanine nucleotide binding site and alternates between an active, GTP-bound state and an inactive, GDP-bound state. Signaling by an activated GPCR promotes GDP release and GTP binding. The alpha subunit has a low GTPase activity that converts bound GTP to GDP, thereby terminating the signal. Both GDP release and GTP hydrolysis are modulated by numerous regulatory proteins (By similarity). Signaling is mediated via effector proteins, such as adenylate cyclase. Inhibits adenylate cyclase activity, leading to decreased intracellular cAMP levels (By similarity). The inactive GDP-bound form prevents the association of RGS14 with centrosomes and is required for the translocation of RGS14 from the cytoplasm to the plasma membrane. Required for normal cytokinesis during mitosis (By similarity). Required for cortical dynein-dynactin complex recruitment during metaphase (By similarity).[UniProtKB:P10824][UniProtKB:P63096] [ADA2A_HUMAN] Alpha-2 adrenergic receptors mediate the catecholamine-induced inhibition of adenylate cyclase through the action of G proteins. The rank order of potency for agonists of this receptor is oxymetazoline > clonidine > epinephrine > norepinephrine > phenylephrine > dopamine > p-synephrine > p-tyramine > serotonin = p-octopamine. For antagonists, the rank order is yohimbine > phentolamine = mianserine > chlorpromazine = spiperone = prazosin > propanolol > alprenolol = pindolol.[1] Publication Abstract from PubMedThe alpha2 adrenergic receptors (alpha2ARs) are G protein-coupled receptors (GPCRs) that respond to adrenaline and noradrenaline and couple to the Gi/o family of G proteins. alpha2ARs play important roles in regulating the sympathetic nervous system. Dexmedetomidine is a highly selective alpha2AR agonist used in post-operative patients as an anxiety-reducing, sedative medicine that decreases the requirement for opioids. As is typical for selective alphaAR agonists, dexmedetomidine consists of an imidazole ring and a substituted benzene moiety lacking polar groups, which is in contrast to betaAR-selective agonists, which share an ethanolamine group and an aromatic system with polar, hydrogen-bonding substituents. To better understand the structural basis for the selectivity and efficacy of adrenergic agonists, we determined the structure of the alpha2BAR in complex with dexmedetomidine and Go at a resolution of 2.9 A by single-particle cryo-EM. The structure reveals the mechanism of alpha2AR-selective activation and provides insights into Gi/o coupling specificity. Activation of the alpha2B adrenoceptor by the sedative sympatholytic dexmedetomidine.,Yuan D, Liu Z, Kaindl J, Maeda S, Zhao J, Sun X, Xu J, Gmeiner P, Wang HW, Kobilka BK Nat Chem Biol. 2020 Mar 9. pii: 10.1038/s41589-020-0492-2. doi:, 10.1038/s41589-020-0492-2. PMID:32152538[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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