G protein-coupled receptors articles within Nature Communications

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  • Article
    | Open Access

    The glucagon-like peptide-1 (GLP-1) receptor is a key regulator of glucose homeostasis and a drug target for type 2 diabetes but available GLP-1R agonists are suboptimal due to several side-effects. Here authors report the cryo-EM structure of GLP-1R bound to an ago-allosteric modulator in complex with heterotrimeric Gs which offers insights into the molecular details of ago-allosterism.

    • Zhaotong Cong
    • , Li-Nan Chen
    •  & Ming-Wei Wang

  • Article
    | Open Access

    Human leukotriene B4 receptors (BLT1 and BLT2) are members of the GPCR superfamily that respond to a potent pro-inflammatory lipid and chemoattractant LTB4. Here authors determined a crystal structure of the human BLT1 in complex with a selective antagonist MK-D-046 and provide insights into hBLT1 ligand recognition and its mechanism of action.

    • Nairie Michaelian
    • , Anastasiia Sadybekov
    •  & Vadim Cherezov

  • Article
    | Open Access

    The human neuropeptide Y receptor Y2 (Y2R) is a drug target for the treatment of obesity and anxiety. Crystal structure of Y2R bound to a selective antagonist and accompanying mutagenesis provide insights into ligand recognition and subtype specificity of NPY receptors.

    • Tingting Tang
    • , Christin Hartig
    •  & Beili Wu

  • Article
    | Open Access

    The dopamine D2 receptor (D2R) is a GPCR and an important drug target for schizophrenia treatment. Here, the authors present the crystal structure of human D2R in complex with the antipsychotic drug spiperone, which is of interest for designing antipsychotics with improved receptor selectivity.

    • Dohyun Im
    • , Asuka Inoue
    •  & Tatsuro Shimamura

  • Article
    | Open Access

    The human gonadotropin-releasing hormone receptor GnRH1R is a GPCR with an important role in the human reproductive system and of interest as a drug target. Here, the authors present the 2.8 Å crystal structure of human GnRH1R with the high affinity antagonist drug Elagolix and the observed unusual ligand binding mode was further analysed with functional assays and molecular docking studies.

    • Wei Yan
    • , Lin Cheng
    •  & Zhenhua Shao

  • Article
    | Open Access

    Growth hormone-releasing hormone (GHRH) controls metabolism and tissue growth through binding to the cognate receptor (GHRHR). Here authors report the structure of the human GHRHR bound to its endogenous ligand and the stimulatory G protein which reveals a characteristic hormone recognition pattern of GHRH by GHRHR.

    • Fulai Zhou
    • , Huibing Zhang
    •  & Ming-Wei Wang

  • Article
    | Open Access

    Vasoactive intestinal polypeptide receptor (VIP1R) is a widely expressed class B G protein-coupled receptor and a drug target for the treatment of inflammatory diseases. Here authors report a cryoelectron microscopy structure of human VIP1R bound to PACAP27 and Gs heterotrimer, which provides insights into PACAP27 binding and VIP receptor activation.

    • Jia Duan
    • , Dan-dan Shen
    •  & Yi Jiang

  • Article
    | Open Access

    Chemokine receptors are GPCRs involved in immune responses and regulated by small protein ligands known as chemokines. A structural study of the human CCR6/CCL20–Go complex reveals that CCL20 binds in a shallow extracellular pocket, and suggests that activation of CCR6 by CCL20 binding involves an allosteric effect on a noncanonical toggle switch.

    • David Jonathan Wasilko
    • , Zachary Lee Johnson
    •  & Huixian Wu

  • Article
    | Open Access

    Glucagon-like peptide-1 receptor (GLP-1R) plays an important role in glucose homeostasis and treatment of type 2 diabetes. Here authors report the peptide-free crystal structure of human GLP-1R in an inactive state which reveals a unique closed conformation of the extracellular domain.

    • Fan Wu
    • , Linlin Yang
    •  & Raymond C. Stevens

  • Article
    | Open Access

    Formyl peptide receptors (FPRs) are GPCRs that play important roles in transducing chemotactic signals in phagocytes and mediating host-defense and inflammatory responses. Here the authors present the 2.8 Å crystal structure of human FPR2 in complex with the peptide agonist WKYMVm and in combination with molecular docking, ligand-binding and signalling assays provide further insights into the binding modes of FPR2 to both non-formyl and formyl peptides.

    • Tong Chen
    • , Muya Xiong
    •  & Beili Wu

  • Article
    | Open Access

    Detergents are indispensable reagents in membrane protein structural biology. Here, L. H. Urner and co-workers introduce oligoglycerol detergents (OGDs) and use native mass spectrometry to show how interactions of membrane proteins with native membrane lipids can be preserved during purification.

    • Leonhard H. Urner
    • , Idlir Liko
    •  & Kevin Pagel

  • Article
    | Open Access

    WNT-Frizzled (FZD) signaling plays a critical role in embryonic development, tissue homeostasis and human disease but no small molecule drugs targeting FZD with distinct efficacy have emerged so far. Here, authors identify the Smoothened agonist SAG1.3 as a partial agonist for FZD6 with limited subtype selectivity.

    • Paweł Kozielewicz
    • , Ainoleena Turku
    •  & Gunnar Schulte

  • Article
    | Open Access

    The extracellular regions (ECRs) of adhesion GPCRs have diverse biological functions, but their structures and mechanisms of action remain unclear. Here, the authors solve the ECR structure of the Gpr126 receptor and show that ECR conformation and signaling functions are regulated by alternative splicing.

    • Katherine Leon
    • , Rebecca L. Cunningham
    •  & Demet Araç

  • Article
    | Open Access

    Cysteinyl leukotriene G protein-coupled receptors CysLT1 and CysLT2 regulate pro-inflammatory responses associated with allergic disorders. Here, authors describe four crystal structures of CysLT2R in complex with three dual CysLT1R/CysLT2R antagonists, which shed light on CysLTR ligand selectivity.

    • Anastasiia Gusach
    • , Aleksandra Luginina
    •  & Vadim Cherezov

  • Article
    | Open Access

    Palmitoylation is a post translational modification that regulates GPCR activity. Here the authors show that palmitoylation of 5-HT1AR by the palmitoyltransferase enzyme ZDHHC21 contributes to depression-like behaviour in rodents and might be implicated in major depressive disorder.

    • Nataliya Gorinski
    • , Monika Bijata
    •  & Evgeni Ponimaskin

  • Article
    | Open Access

    Allosteric GPCR modulators can achieve exquisite subtype selectivity, but the underlying mechanism is unclear. Using molecular dynamics simulations, the authors here identify a previously undetected dynamic pocket in muscarinic GPCRs that is critical for subtype selectivity of allosteric modulators.

    • Scott A. Hollingsworth
    • , Brendan Kelly
    •  & Ron O. Dror

  • Article
    | Open Access

    In the healthy heart, the β2 adrenergic receptor (β2AR) signals through Gs and Gi proteins but the mechanism underlying G protein selectivity is not fully understood. Here, the authors show that membrane charge and intracellular cations modulate the β2AR−Gi3 interaction.

    • M. J. Strohman
    • , S. Maeda
    •  & B. K. Kobilka

  • Article
    | Open Access

    The cellular functions of arrestins are determined in part by the pattern of phosphorylation on the G protein-coupled receptors (GPCRs) to which arrestins bind. Here, authors use a library of synthetic phosphopeptide analogues of the GPCR rhodopsin C-terminus and determine the ability of these peptides to bind and activate arrestins using a variety of biochemical and biophysical methods.

    • Daniel Mayer
    • , Fred F. Damberger
    •  & Dmitry B. Veprintsev

  • Article
    | Open Access

    Class F receptors are therapeutic targets in human disease and understanding their structural changes during receptor activation may provide important pharmacological insight. Here, the authors combine computational and experimental methods to identify a molecular switch in TM6/7 of Class F receptors that mediates receptor activation.

    • Shane C. Wright
    • , Paweł Kozielewicz
    •  & Gunnar Schulte

  • Article
    | Open Access

    Neurokinin receptors are G protein-coupled receptors. Here the authors present three crystal structures of the neurokinin 1 receptor (NK1R) in complex with small-molecule antagonists including aprepitant and netupitant and observe that these clinically approved compounds induce a conformational change in the receptor.

    • Jendrik Schöppe
    • , Janosch Ehrenmann
    •  & Andreas Plückthun

  • Article
    | Open Access

    The determination of high resolution structures of G protein coupled receptors (GPCRs) in complex with heterotrimeric G proteins is challenging. Here authors develop an antibody fragment, mAB16, which stabilizes GPCR/G-protein complexes and facilitates the application of high resolution cryo-EM.

    • Shoji Maeda
    • , Antoine Koehl
    •  & Brian K. Kobilka

  • Article
    | Open Access

    Evidence suggests oligomerisation of G protein-coupled receptors in membranes, but this is controversial. Here, authors use single-molecule and ensemble FRET, and spectroscopy to show that the neurotensin receptor 1 forms multiple dimer conformations that interconvert - “rolling” interfaces.

    • Patricia M. Dijkman
    • , Oliver K. Castell
    •  & Anthony Watts

  • Article
    | Open Access

    Opsins are G protein-coupled receptors which are activated by light-triggered retinal 11-cis-to-all-trans photoisomerization. Here, the authors report a vertebrate non-visual opsin (Opn5L1) that functions as a Gi-coupled retinal receptor, is deactivated by light and can thermally self-regenerate.

    • Keita Sato
    • , Takahiro Yamashita
    •  & Yoshinori Shichida

  • Article
    | Open Access

    It is unclear whether GPCRs, G proteins and adenylyl cyclase (AC) associate through random collisions or defined pre-coupling mechanisms. Using a peptide-based approach, the authors show that heteromers of adenosine A2A and dopamine D2 receptors form pre-coupled complexes with their cognate G proteins and AC5.

    • Gemma Navarro
    • , Arnau Cordomí
    •  & Sergi Ferré

  • Article
    | Open Access

    Upon stimulation by agonist binding, the C-terminal regions of G-protein-coupled receptors (GPCRs) become phosphorylated by GPCR kinases, and phosphorylated GPCRs bind arrestin. Here the authors give structural insights into the phosphorylation induced conformational changes in GPCRs by performing NMR studies with the β2-adrenoceptor.

    • Yutaro Shiraishi
    • , Mei Natsume
    •  & Ichio Shimada

  • Article
    | Open Access

    β1-adrenergic receptors are expressed in cardiac tissue and stimulated by the sympathetic nervous system. Here, the authors use NMR spectroscopy to unravel the conformational diversity upon β1-adrenergic receptor activation and provide structural insights into partial agonism and basal activity.

    • Andras S. Solt
    • , Mark J. Bostock
    •  & Daniel Nietlispach

  • Article
    | Open Access

    β1 and β2 adrenergic receptors (ARs) are the predominant G protein-coupled receptor subtypes expressed in mammalian hearts. Here the authors describe a signaling mechanism where the biased agonist carvedilol converts β1AR from a classical Gαs-coupled to a Gαi-coupled receptor to mediate β-arrestin-dependent signaling.

    • Jialu Wang
    • , Kenji Hanada
    •  & Howard A. Rockman

  • Article
    | Open Access

    While arrestins are mainly associated with GPCR signaling, arrestin-3 can signal independently of receptor interaction. Here the authors present the structure of arrestin-3 bound to inositol hexakisphosphate (IP6) and propose a model for arrestin-3 activation.

    • Qiuyan Chen
    • , Nicole A. Perry
    •  & T. M. Iverson

  • Article
    | Open Access

    Nutrients taste perception is mediated by T1r receptors that discriminate specific tastes among their wide diversity. Here the authors present crystal structures of the ligand-binding domains of the fish T1r2-T1r3 receptor, providing a structural framework for its ligand recognition.

    • Nipawan Nuemket
    • , Norihisa Yasui
    •  & Atsuko Yamashita

  • Article
    | Open Access

    Beta-arrestins play central roles in the mechanisms regulating GPCR signalling and trafficking. Here the authors identify a selective inhibitor of the interaction between β-arrestin and the β2-adaptin subunit of the clathrin adaptor protein AP-2, which they use to dissect the role of the β-arrestin/β2-adaptin interaction in GPCR signalling.

    • Alexandre Beautrait
    • , Justine S. Paradis
    •  & Michel Bouvier

  • Article
    | Open Access

    The activity of G-protein-coupled receptors is regulated by their interaction with arrestins. Here the authors show that loops located on C-edge of arrestin-1 serve as a membrane anchor during the multi-step binding process that leads to a stable receptor–arrestin complex.

    • Ciara C M. Lally
    • , Brian Bauer
    •  & Martha E Sommer

  • Article
    | Open Access

    G-protein-coupled receptors trigger several signalling pathways and their activity was proposed to be allosteric modulated by cholesterol. Here the authors use molecular dynamics simulations and ligand binding assays to show that membrane cholesterol can bind to adenosine A2Areceptor orthosteric site.

    • Ramon Guixà-González
    • , José L. Albasanz
    •  & Jana Selent

  • Article
    | Open Access

    Angiotensin II type 1 receptor (AT1R)-mediated acute catecholamine release is modulated by β-arrestin. Here the authors show that β-arrestin-1 recruits the Ca2+channel TRPC3 and the PLCγ to the AT1R-β-arrestin complex, triggering G protein-independent calcium influx and catecholamine secretion.

    • Chun-Hua Liu
    • , Zheng Gong
    •  & Jin-Peng Sun

  • Article
    | Open Access

    The atypical chemokine receptor 3 (ACKR3) is important for cell migration in development and cancer. Here the authors combine radiolytic footprinting, disulfide trapping, mutagenesis and molecular modelling to characterize the ligand interactions and ligand-induced conformational changes in ACKR3.

    • Martin Gustavsson
    • , Liwen Wang
    •  & Tracy M. Handel

  • Article
    | Open Access

    β-arrestins initially contact with the phosphorylated carboxyl-terminus of GPCRs before engaging with the GPCR core. Here, the authors use a chimeric GPCR partially and fully engaged with β-arrestin1 and show that the core interaction is dispensable for receptor endocytosis and signalling.

    • Punita Kumari
    • , Ashish Srivastava
    •  & Arun K. Shukla

  • Article
    | Open Access

    Retinitis pigmentosa is often caused by mutations that affect the activity or transport of rhodopsin, but some mutations cause disease even though an apparently functional protein is produced. Here the authors show that three such enigmatic mutants retain scramblase activity but are unable to dimerize.

    • Birgit Ploier
    • , Lydia N. Caro
    •  & Anant K. Menon

  • Article
    | Open Access

    Cellular signaling processes often involve trafficking of receptors and other proteins between subcellular compartments. Here the authors demonstrate a method based on the concept of Enhanced bystander Bioluminescence Resonance Energy Transfer (EbBRET) that allows efficient real time monitoring of endocytosis and trafficking.

    • Yoon Namkung
    • , Christian Le Gouill
    •  & Stéphane A. Laporte

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