G protein-coupled receptors articles within Nature Communications

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  • Article
    | Open Access

    Visualizing endogenous GPCRs is challenging. Here the authors generate mice with an enzyme self-label genome-edited into the endogenous glucagon-like peptide-1 receptor locus, design fluorescent dyes for specific labelling in complex tissue, and reveal tissue-level organisation and dynamics of an endogenous class B GPCR.

    • Julia Ast
    • , Daniela Nasteska
    •  & David J. Hodson

  • Article
    | Open Access

    GPCRs are integral membrane proteins that serve as attractive drug targets. Here, authors delineate the conformational landscapes of 45 GPCRs using a statistical model, highlighting their malleable native ensembles and providing functional insights.

    • Sathvik Anantakrishnan
    •  & Athi N. Naganathan

  • Article
    | Open Access

    Neuromedin U receptor 2 is an emerging attractive target for treating obesity. Here, a Cryo-EM structure of NmU-25–NMU2–Gi1 provides the structural basis for the designation of highly selective drugs.

    • Wenli Zhao
    • , Wenru Zhang
    •  & Qiang Zhao

  • Article
    | Open Access

    G protein coupled receptors (GPCRs) can couple to different Gα protein subfamilies either selectively or promiscuously. Here, the authors use computational approach to show that selectivity determinants are at the periphery of the GPCR—G protein interface and that promiscuous GPCRs more frequently sample the common rather than selective contacts.

    • Manbir Sandhu
    • , Aaron Cho
    •  & Nagarajan Vaidehi

  • Article
    | Open Access

    Agonists selectively targeting GPR119 hold promise for treating metabolic disorders. Here, authors reveal that GPR119 adopts a non-canonical consensus structural scaffold with an extended ligand-binding pocket for chemically different agonists.

    • Yuxia Qian
    • , Jiening Wang
    •  & Anna Qiao

  • Article
    | Open Access

    Previously, peptide selectivity in the VPAC receptor family of GPCRs was poorly understood. Here, authors combine cryo-EM and MD data to understand binding and selectivity of VPAC1R and PAC1R peptide agonists that can guide future drug development.

    • Sarah J. Piper
    • , Giuseppe Deganutti
    •  & Denise Wootten

  • Article
    | Open Access

    Activation of neutrophil leukocytes is tightly regulated, and it is important to understand the molecular mechanisms of their response to physiological and pathological stimuli. Here authors show that the adhesion molecule G protein-coupled receptor 97 and its interaction partners play pivotal roles in neutrophil leukocyte activation both in anti-microbial response and in inflammatory diseases.

    • Tai-Ying Chu
    • , Céline Zheng-Gérard
    •  & Hsi-Hsien Lin

  • Article
    | Open Access

    Subcellular signaling is critical to generating cellular responses that modulate inflammatory pathways at the chemokine receptor CXCR3. Eiger et al. determine that agonist-biased CXCR3 signaling at endosomes differs from that at the plasma membrane, proposing location bias as an important phenomenon in signal transduction.

    • Dylan Scott Eiger
    • , Noelia Boldizsar
    •  & Sudarshan Rajagopal

  • Article
    | Open Access

    S1P5 is a sphingosine-1-phosphate (S1P) receptor implicated in immune and neurodegenerative disorders. Here, authors report a crystal structure of the S1P5 receptor in complex with a selective inverse agonist, revealing an allosteric subpocket and shedding light on inverse agonism in S1P receptors.

    • Elizaveta Lyapina
    • , Egor Marin
    •  & Vadim Cherezov

  • Article
    | Open Access

    Despite its crucial role in the central nervous system, little is known about the activation mechanism of GABAB receptor. Here, the authors predict that the inactive G protein induces conformational changes of the receptor to form an intermediate state.

    • Moon Young Yang
    • , Soo-Kyung Kim
    •  & William A. Goddard III

  • Article
    | Open Access

    Here, Waltenspühl et al. report the cryo-EM structure of active human oxytocin receptor in complex with oxytocin and with a heterotrimeric G protein, providing insights into this hormone system critically involved in the regulation of social behaviour and reproduction.

    • Yann Waltenspühl
    • , Janosch Ehrenmann
    •  & Andreas Plückthun

  • Article
    | Open Access

    D1 dopamine receptor is an important drug target for treatment of hypertension and Parkinson’s disease. Here, authors report three cryo-EM structures of the D1R-Gs complex bound to three distinct D1R-selective drugs.

    • Xiao Teng
    • , Sijia Chen
    •  & Sanduo Zheng

  • Article
    | Open Access

    The OX2 orexin receptor (OX2R) is a brain GPCR that regulates wakefulness and circadian rhythms in humans, and a potential drug target in insomnia and narcolepsy. Here, the authors use cryo-EM to determine how the first clinically tested OX2R agonist TAK-925 can activate OX2R in a selective manner.

    • Jie Yin
    • , Yanyong Kang
    •  & Daniel M. Rosenbaum

  • Article
    | Open Access

    The authors report the structural characterization of M4R selective allosteric agonist, compound-110, as well as agonist iperoxo and positive allosteric modulator LY2119620. The cryo-EM structures of compound-110, iperoxo or iperoxo-LY2119620 bound M4R-Gi complex reveal different interaction modes and activation mechanisms of M4R. An antipsychotic activity of compound-110 with low extrapyramidal side effects in a schizophrenia-mimic mouse model is also reported. Thus, the study provides structural insights for selectively targeting mAChRs subtypes.

    • Jingjing Wang
    • , Meng Wu
    •  & Tian Hua

  • Article
    | Open Access

    GPR88 is an orphan GPCR and regulates diverse brain functions. Here, the authors report two structures of the human GPR88-Gi complex, showing an allosteric ligand directly involved in the interaction interface between the receptor and G-protein, and a density which may represent an endogenous ligand of GPR88.

    • Geng Chen
    • , Jun Xu
    •  & Yang Du

  • Article
    | Open Access

    Direct information on the dynamic interplay between membrane proteins and lipids is scarce. Here the authors report a detailed description of these close relationships by combining lipid nanodiscs and high-pressure NMR. They report the link between pressure and lipid compositions to the conformational landscape of the β-barrel OmpX and the α-helical BLT2 G Protein-Coupled Receptor in nanodiscs.

    • Alexandre Pozza
    • , François Giraud
    •  & Laurent J. Catoire

  • Article
    | Open Access

    The formyl peptide receptor 2 (FPR2) is involved in the pathogenesis of Alzheimer’s disease. Structures of FPR2 bound to Aβ42, humanin, or formyl peptides offer insight into Aβ42 neurotoxicity, humanin neuroprotection, and FPR ligand selectivity

    • Ya Zhu
    • , Xiaowen Lin
    •  & Beili Wu

  • Article
    | Open Access

    The human neuropeptide Y (NPY) acts through G-protein coupled receptors and is involved in food intake, stress response, anxiety, and memory retention. Here, the authors show that, unlike in other neuropeptides, both the N-terminal and the C-terminal regions of NPY interact with the NPY receptor 1.

    • Chaehee Park
    • , Jinuk Kim
    •  & Hee-Jung Choi

  • Article
    | Open Access

    Type 2 bradykinin receptor (B2R) is essential in vasodilation and cardioprotection. Here the authors present two cryo-EM structures of human B2R-Gq in complex with bradykinin and kallidin to elucidate the mechanisms for ligand binding, receptor activation, and Gq proteins coupling.

    • Jinkang Shen
    • , Dongqi Zhang
    •  & Haitao Zhang

  • Article
    | Open Access

    The mechanism of CGRP-evoked peripheral pain is unclear. Here, the authors show that the CGRP-mediated neuronal/Schwann cell pathway mediates allodynia associated with neurogenic inflammation, contributing to the algesic action of CGRP in mice.

    • Francesco De Logu
    • , Romina Nassini
    •  & Pierangelo Geppetti

  • Article
    | Open Access

    GPCR kinases (GRKs) phosphorylate active-form G-protein-coupled receptors (GPCRs). Here, the authors reveal that Gq heterotrimer coupled with the angiotensin II type-1 receptor (AT1R) determines the GRK subtypes recruited to the complex in a microdomain, thus defining subsequent AT1R phosphorylation patterns, β-arrestin conformation and functionality.

    • Kouki Kawakami
    • , Masataka Yanagawa
    •  & Asuka Inoue

  • Article
    | Open Access

    Melatonin receptors (MT1 and MT2) are the targets for melatonin, the major neurohormone involved in circadian rhythm and sleep regulation. Here the authors describe the structures of 2-iodomelatonin and ramelteon bound MT1–Gi and MT2-Gi, revealing that MT1 and MT2 possess distinctive features within the ligand-binding pocket.

    • Qinggong Wang
    • , Qiuyuan Lu
    •  & Yuyong Tao

  • Article
    | Open Access

    Ghrelin receptor regulates energy homeostasis through constitutive activity or by the ghrelin. Here the authors report two structures of ghrelin receptor bound to agonist and inverse agonist, providing insights into the mechanism of inverse agonism, which is of interest for specific ligand design.

    • Jiao Qin
    • , Ye Cai
    •  & Zhenhua Shao

  • Article
    | Open Access

    The glucagon-like peptide-1 receptor (GLP-1R) can be targeted in the treatment of diabetes, obesity and other metabolic disorders. Here, the authors assess the molecular mechanisms of peptide agonists binding to GLP-1R and the responses elucidated by these ligands, including distinct kinetics of G protein activation.

    • Giuseppe Deganutti
    • , Yi-Lynn Liang
    •  & Denise Wootten

  • Article
    | Open Access

    Here, the authors use high-speed atomic force microscopy (HS-AFM) methods to characterize the single molecule kinetics of wild-type bacteriorhodopsin (bR) with millisecond temporal resolution, providing new insights into the bR conformational cycle.

    • Alma P. Perrino
    • , Atsushi Miyagi
    •  & Simon Scheuring

  • Article
    | Open Access

    β-arrestins commonly bind to two distinct elements in GPCRs: the phosphorylated carboxyl terminal tail (C tail) and the cytoplasmic face of the transmembrane region (TM core). Here, the authors use methyl-TROSY NMR measurements to characterise the interactions between β-arrestin 1 (βarr1) and a GPCR and observe that C tail-mediated interaction with a GPCR alone induces the partial activation of βarr1, whereas the TM core- and C tail-mediated interactions together stabilize the activated conformation of βarr1.

    • Yutaro Shiraishi
    • , Yutaka Kofuku
    •  & Ichio Shimada

  • Article
    | Open Access

    The orphan GPR158 receptor belongs to the class C GPCR family and interacts with the regulator of G protein signaling 7 (RGS7)-Gβ5 complex. Here, the authors present the cryo-EM structure of human GPR158, which reveals that the extracellular domain contains a PAS domain, and they also determine the structures of GPR158 in complex with either one or two RGS7-Gβ5 heterodimers and discuss implications for the signaling mechanism.

    • Eunyoung Jeong
    • , Yoojoong Kim
    •  & Yunje Cho

  • Article
    | Open Access

    Nutrient status in the cell regulates autophagy via mTORC1 activity. Here, the authors show that the ubiquitous G protein subunit Gαq contributes to nutrient sensing by promoting formation of an mTOR-p62-Raptor complex in replete conditions, modulating autophagy.

    • Sofía Cabezudo
    • , Maria Sanz-Flores
    •  & Catalina Ribas

  • Article
    | Open Access

    Pannexin 1 (PANX1) is a membrane channel mediating release of signaling molecules to the extracellular space. PANX1 can be activated by GPCRs. Here, the authors elucidate a non-canonical channel activation pathway by α1-adrenergic receptor that involves HDAC6- mediated lysine deacetylation of PANX1.

    • Yu-Hsin Chiu
    • , Christopher B. Medina
    •  & Douglas A. Bayliss

  • Article
    | Open Access

    The cryo-EM structure of pentameric green-light absorbing proteorhodopsin together with molecular dynamics simulations and functional studies provides insights into the proton translocation pathway and oligomerization, and a protonation-dependent mechanism for intracellular half channel hydration.

    • Stephan Hirschi
    • , David Kalbermatter
    •  & Dimitrios Fotiadis

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