7ul3
From Proteopedia
CryoEM Structure of Inactive H2R Bound to Famotidine, Nb6M, and NabFab
Structural highlights
FunctionOPRK_HUMAN G-protein coupled opioid receptor that functions as receptor for endogenous alpha-neoendorphins and dynorphins, but has low affinity for beta-endorphins. Also functions as receptor for various synthetic opioids and for the psychoactive diterpene salvinorin A. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling leads to the inhibition of adenylate cyclase activity. Inhibits neurotransmitter release by reducing calcium ion currents and increasing potassium ion conductance. Plays a role in the perception of pain. Plays a role in mediating reduced physical activity upon treatment with synthetic opioids. Plays a role in the regulation of salivation in response to synthetic opioids. May play a role in arousal and regulation of autonomic and neuroendocrine functions.[1] [2] [3] [4] HRH2_HUMAN The H2 subclass of histamine receptors mediates gastric acid secretion. Also appears to regulate gastrointestinal motility and intestinal secretion. Possible role in regulating cell growth and differentiation. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase and, through a separate G protein-dependent mechanism, the phosphoinositide/protein kinase (PKC) signaling pathway (By similarity). Publication Abstract from PubMedCryogenic electron microscopy (cryo-EM) has widened the field of structure-based drug discovery by allowing for routine determination of membrane protein structures previously intractable. Despite representing one of the largest classes of therapeutic targets, most inactive-state G protein-coupled receptors (GPCRs) have remained inaccessible for cryo-EM because their small size and membrane-embedded nature impedes projection alignment for high-resolution map reconstructions. Here we demonstrate that the same single-chain camelid antibody (nanobody) recognizing a grafted intracellular loop can be used to obtain cryo-EM structures of inactive-state GPCRs at resolutions comparable or better than those obtained by X-ray crystallography. Using this approach, we obtained structures of neurotensin 1 receptor bound to antagonist SR48692, mu-opioid receptor bound to alvimopan, apo somatostatin receptor 2 and histamine receptor 2 bound to famotidine. We expect this rapid, straightforward approach to facilitate the broad exploration of GPCR inactive states without the need for extensive engineering and crystallization. Structure determination of inactive-state GPCRs with a universal nanobody.,Robertson MJ, Papasergi-Scott MM, He F, Seven AB, Meyerowitz JG, Panova O, Peroto MC, Che T, Skiniotis G Nat Struct Mol Biol. 2022 Dec;29(12):1188-1195. doi: 10.1038/s41594-022-00859-8. , Epub 2022 Nov 17. PMID:36396979[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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