7u2l
C5guano-uOR-Gi-scFv16
Structural highlights
FunctionGNAI1_HUMAN Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems. The G(i) proteins are involved in hormonal regulation of adenylate cyclase: they inhibit the cyclase in response to beta-adrenergic stimuli. 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. May play a role in cell division.[1] [2] Publication Abstract from PubMedMu-opioid receptor (microOR) agonists such as fentanyl have long been used for pain management, but are considered a major public health concern owing to their adverse side effects, including lethal overdose(1). Here, in an effort to design safer therapeutic agents, we report an approach targeting a conserved sodium ion-binding site(2) found in microOR(3) and many other class A G-protein-coupled receptors with bitopic fentanyl derivatives that are functionalized via a linker with a positively charged guanidino group. Cryo-electron microscopy structures of the most potent bitopic ligands in complex with microOR highlight the key interactions between the guanidine of the ligands and the key Asp(2.50) residue in the Na(+) site. Two bitopics (C5 and C6 guano) maintain nanomolar potency and high efficacy at G(i) subtypes and show strongly reduced arrestin recruitment-one (C6 guano) also shows the lowest G(z) efficacy among the panel of microOR agonists, including partial and biased morphinan and fentanyl analogues. In mice, C6 guano displayed microOR-dependent antinociception with attenuated adverse effects, supporting the microOR sodium ion-binding site as a potential target for the design of safer analgesics. In general, our study suggests that bitopic ligands that engage the sodium ion-binding pocket in class A G-protein-coupled receptors can be designed to control their efficacy and functional selectivity profiles for G(i), G(o) and G(z) subtypes and arrestins, thus modulating their in vivo pharmacology. Structure-based design of bitopic ligands for the micro-opioid receptor.,Faouzi A, Wang H, Zaidi SA, DiBerto JF, Che T, Qu Q, Robertson MJ, Madasu MK, El Daibani A, Varga BR, Zhang T, Ruiz C, Liu S, Xu J, Appourchaux K, Slocum ST, Eans SO, Cameron MD, Al-Hasani R, Pan YX, Roth BL, McLaughlin JP, Skiniotis G, Katritch V, Kobilka BK, Majumdar S Nature. 2023 Jan;613(7945):767-774. doi: 10.1038/s41586-022-05588-y. Epub 2022 , Nov 30. PMID:36450356[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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