7ul2 | pdb_00007ul2
CryoEM Structure of Inactive NTSR1 Bound to SR48692 and Nb6
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] NTR1_HUMAN Receptor for the tridecapeptide neurotensin. It is associated with G proteins that activate a phosphatidylinositol-calcium second messenger system. 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. See AlsoReferences
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