G protein-coupled receptors articles within Nature Communications

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• Article
  20 March 2024 | Open Access

  Structural basis of ligand recognition and design of antihistamines targeting histamine H₄ receptor

  The histamine H₄ receptor (H₄R) plays key roles in immune cell function. Here, the authors report structures of H₄R-Gi complex with various ligands bound, revealing distinct ligand binding modes and a basis for rational design of novel antihistamines targeting H₄R.

  • Ruixue Xia
  • , Shuang Shi
  •  & Yuanzheng He

• Article
  05 March 2024 | Open Access

  Specific pharmacological and G_i/o protein responses of some native GPCRs in neurons

  G protein responses mediated by GPCRs may differ depending on their environment. Here, using highly sensitive Gi/o sensors, the authors reveal the specific pharmacological and Gi/o protein responses of some native GPCRs in neurons, and the influence of G protein composition.

  • Chanjuan Xu
  • , Yiwei Zhou
  •  & Jianfeng Liu

• Article
  02 March 2024 | Open Access

  Structure-guided engineering of biased-agonism in the human niacin receptor via single amino acid substitution

  GPR109A is a prototypical GPCR and a key drug target for dyslipidemia. Here, the authors present cryo-EM structures of this receptor to elucidate agonist-binding and activation, and design receptor mutants with transducer-coupling-bias.

  • Manish K. Yadav
  • , Parishmita Sarma
  •  & Arun K. Shukla

• Article
  28 February 2024 | Open Access

  Cryo-EM structure of cell-free synthesized human histamine 2 receptor/G_s complex in nanodisc environment

  The study describes the molecular structure of the human histamine 2 receptor in active conformation and in complex with G_s heterotrimer, synthesized in a cell-free system and co-translationally inserted into preformed nanodiscs.

  • Zoe Köck
  • , Kilian Schnelle
  •  & Frank Bernhard

• Article
  13 February 2024 | Open Access

  Binding kinetics drive G protein subtype selectivity at the β₁-adrenergic receptor

  The authors show G protein subtype selectivity at the β₁-adrenergic receptor is driven by the binding kinetics of ternary complex formation. Bound to G protein, the receptor adopts conformations that differ from its agonist-bound solution states.

  • Andrew J. Y. Jones
  • , Thomas H. Harman
  •  & Daniel Nietlispach

• Article
  07 February 2024 | Open Access

  Structural basis for lysophosphatidylserine recognition by GPR34

  GPR34 is a GPCR which has an immunomodulatory role and recognizes lysophosphatidylserine (LysoPS) as a putative endogenous ligand. Here, authors report two cryo-EM structures of human GPR34-Gi complex with one of two ligands bound: either the LysoPS analogue S3E-LysoPS, or its derivative M1.

  • Tamaki Izume
  • , Ryo Kawahara
  •  & Osamu Nureki

• Article
  02 January 2024 | Open Access

  Molecular mechanism of antihistamines recognition and regulation of the histamine H₁ receptor

  Histamine receptor H₁R has been extensively targeted in the development of antihistamines. Here, Wang et al. determine structures of H₁R alone and bound to different antihistamines, providing insights into the structure-based design of next-generation drugs.

  • Dandan Wang
  • , Qiong Guo
  •  & Yuyong Tao

• Article
  02 January 2024 | Open Access

  Molecular basis of human trace amine-associated receptor 1 activation

  hTA1 is a drug target for several neuropsychiatric disorders. Using cryo-EM and pharmacological assays, the authors illuminate hTA1’s similarity to neurotransmitter receptors and discover that the antipsychotic asenapine potently activates the receptor.

  • Gregory Zilberg
  • , Alexandra K. Parpounas
  •  & Daniel Wacker

• Article
  09 December 2023 | Open Access

  Unravelling the mechanism of neurotensin recognition by neurotensin receptor 1

  GPCRs include inactive and active states. ¹⁹F-NMR and stopped-flow fluorescence kinetic assays reveal that neurotensin activates the prototypical peptide-binding GPCR, neurotensin receptor 1, through an induced-fit mechanism, where ligand binding precedes receptor conformational changes.

  • Kazem Asadollahi
  • , Sunnia Rajput
  •  & Paul R. Gooley

• Article
  08 December 2023 | Open Access

  Structures of human prostaglandin F_2α receptor reveal the mechanism of ligand and G protein selectivity

  Cryo-EM structures reveal the molecular mechanism of ligands and G protein selectivity for prostaglandin F_2α receptor, providing guidance for development of better postpartum hemorrhage drugs.

  • Xiuqing Lv
  • , Kaixuan Gao
  •  & Xiangyu Liu

• Article
  01 December 2023 | Open Access

  Structural basis of antibody inhibition and chemokine activation of the human CC chemokine receptor 8

  CCR8 is a promising target in cancer immunotherapy. Here, authors generated mAb1, an antagonist antibody against CCR8 and determined structures of CCR8 in complex with mAb1 or the agonist CCL1, providing insights into CCR8 inhibition and activation.

  • Dawei Sun
  • , Yonglian Sun
  •  & Matthieu Masureel

• Matters Arising
  30 November 2023 | Open Access

  Reply to: How carvedilol does not activate β₂-adrenoceptors

  • Evi Kostenis
  • , Jesus Gomeza
  •  & Stefan Schulz

• Article
  29 November 2023 | Open Access

  Distinct activation mechanisms of β-arrestin-1 revealed by ¹⁹F NMR spectroscopy

  The molecular basis for the functional versatility of β-arrestins in the G-protein coupled receptor signaling pathway is not well understood. Here, the authors use¹⁹F NMR spectroscopy to show that different binding partners activate β-arrestin-1 through distinct mechanisms.

  • Ruibo Zhai
  • , Zhuoqi Wang
  •  & Yunfei Hu

• Article
  22 November 2023 | Open Access

  Orthosteric and allosteric modulation of human HCAR2 signaling complex

  Hydroxycarboxylic acid receptor 2 (HCAR2) has been implicated in cardiovascular and neuroinflammatory diseases. Here, the authors present cryo-EM structures of HCAR2-Gi1 complexes bound to different ligands and provide insights into the mechanisms of both orthosteric and allosteric modulation of HCAR2.

  • Chunyou Mao
  • , Mengru Gao
  •  & Yan Zhang

• Article
  06 November 2023 | Open Access

  Structural basis for ligand recognition and signaling of hydroxy-carboxylic acid receptor 2

  Niacin is used to treat cardiovascular disease through its activation of the GPCR HCAR2. Here, the authors present cryo-EM structures of HCAR2 bound to niacin and other drug-like small molecules, which explain the basis of HCAR2 ligand recognition.

  • Jae-Hyun Park
  • , Kouki Kawakami
  •  & Sam-Yong Park

• Article
  20 October 2023 | Open Access

  Structural insights into the agonists binding and receptor selectivity of human histamine H₄ receptor

  Histamine receptor H₄R is implicated in chronic inflammatory diseases, such as asthma, arthritis, and atopic dermatitis. Here, the authors determined the first cryo-EM structure of the histamine H4 receptor, providing valuable structural insights for the design of drugs targeting H4R in chronic inflammatory diseases.

  • Dohyun Im
  • , Jun-ichi Kishikawa
  •  & So Iwata

• Article
  13 October 2023 | Open Access

  Structural basis of dimerization of chemokine receptors CCR5 and CXCR4

  Here, authors report chemokine receptors structures obtained using coarse-grained metadynamics. CCR5 and CXCR4 homo- and heterodimers differ in the conformations of ligand binding sites and of the G protein interaction interface, suggesting structural basis for the rational design of biased ligands.

  • Daniele Di Marino
  • , Paolo Conflitti
  •  & Vittorio Limongelli

• Article
  09 October 2023 | Open Access

  GLP-1R signaling neighborhoods associate with the susceptibility to adverse drug reactions of incretin mimetics

  Agonists of the glucagon-like peptide-1 receptor are used to treat diabetes and obesity. Here, Wright et al. investigate the subcellular location of the receptor’s signaling events and uncover associations between signaling profiles and adverse drug reactions.

  • Shane C. Wright
  • , Aikaterini Motso
  •  & Volker M. Lauschke

• Article
  23 September 2023 | Open Access

  An inverse agonist of orphan receptor GPR61 acts by a G protein-competitive allosteric mechanism

  GPR61 is an orphan GPCR of interest for treatment of appetite disorders, such as obesity and cachexia. Here, the authors report structures of GPR61 in its active and inactive states, including with a G protein-competitive small molecule inverse agonist.

  • Joshua A. Lees
  • , João M. Dias
  •  & Seungil Han

• Article
  22 September 2023 | Open Access

  Structural basis of hydroxycarboxylic acid receptor signaling mechanisms through ligand binding

  Hydroxy-carboxylic acid receptor (HCA) is an attractive drug target for neuroinflammation. Here, authors report cryo-EM structures of the HCA2 and HCA3-Gi complexes with multiple ligands, to describe the drug recognition and subtype selectivity.

  • Shota Suzuki
  • , Kotaro Tanaka
  •  & Yoshinori Fujiyoshi

• Article
  22 September 2023 | Open Access

  Specific binding of GPR174 by endogenous lysophosphatidylserine leads to high constitutive G_s signaling

  A number of orphan GPCRs show high constitutive activity. Here, the authors show that the high basal activity of some receptors can be explained by their sensitivity to naturally abundant lipids or by penetration of ECL2 in the orthosteric binding pocket.

  • Yingying Nie
  • , Zeming Qiu
  •  & Sanduo Zheng

• Article
  25 August 2023 | Open Access

  Structural basis for the allosteric modulation of rhodopsin by nanobody binding to its extracellular domain

  G protein-coupled receptors (GPCRs) are involved in many physiological processes and are targets of intense drug discovery research. Here, the authors describe llama-derived nanobodies that allosterically modulate rhodopsin, a prototypical GPCR.

  • Arum Wu
  • , David Salom
  •  & Krzysztof Palczewski

• Article
  17 August 2023 | Open Access

  Ligand recognition and G protein coupling of the human itch receptor MRGPRX1

  MRGPRX1 is a key GPCR expressed in the DRG for itch perception, generating scratch or avoidance behaviors. Here, authors provide structural and pharmacological insights into itch sensation, activation and G-protein signaling downstream of MRGPRX1.

  • Lulu Guo
  • , Yumu Zhang
  •  & Jin-Peng Sun

• Article
  09 August 2023 | Open Access

  Molecular insights into intrinsic transducer-coupling bias in the CXCR4-CXCR7 system

  Chemokine receptors are G protein-coupled receptors (GPCRs) involved in immune responses and characterized by ligand promiscuity Here, the authors characterize signaling through chemokine receptors CXCR4 and CXCR7, with insights into intrinsic-bias encoded in the CXCR4-CXCR7 system.

  • Parishmita Sarma
  • , Carlo Marion C. Carino
  •  & Arun K. Shukla

• Article
  04 August 2023 | Open Access

  Membrane mediated mechanical stimuli produces distinct active-like states in the AT1 receptor

  The AT1 GPCR plays an essential role in cardiovascular regulation and may be activated by the peptide AngII as well as membrane stretch. Here, Poudel et al. use molecular simulations to show that membrane-mediated activation produces distinct active-like conformations when compared to activation by AngII.

  • Bharat Poudel
  • , Rajitha Rajeshwar T
  •  & Juan M. Vanegas

• Article
  19 July 2023 | Open Access

  GPCRome-wide analysis of G-protein-coupling diversity using a computational biology approach

  Selective GPCR-G protein complexes formation is critical for signal transduction regulation. Here, the authors use a data-driven approach to show that the structures of experimental and predicted complex interfaces inform, at least partially, on G protein binding preferences.

  • Marin Matic
  • , Pasquale Miglionico
  •  & Francesco Raimondi

• Article
  11 July 2023 | Open Access

  Structural basis of CXC chemokine receptor 1 ligand binding and activation

  Chemokines are small proteins secreted at sites of injury. Here, the authors describe the structure of the chemokine receptor CXCR1 bound to chemokine CXCL8, solved by cryo-EM. The model helps explain the ligand preferences of this receptor.

  • Naito Ishimoto
  • , Jae-Hyun Park
  •  & Sam-Yong Park

• Article
  05 July 2023 | Open Access

  Profiling of basal and ligand-dependent GPCR activities by means of a polyvalent cell-based high-throughput platform

  Interrogating the dynamic and functionally diverse signaling of GPCRs requires comprehensive cellular tools. Here Zeghal et al. develop Tango-Trio, a screening platform capable of profiling basal and drug-activated activities at hundreds of GPCRs.

  • Manel Zeghal
  • , Geneviève Laroche
  •  & Patrick M. Giguère

• Article
  20 June 2023 | Open Access

  Structural basis of α_1A-adrenergic receptor activation and recognition by an extracellular nanobody

  α_1A-adrenergic receptor (α_1AAR) regulates smooth muscle contraction and cognitive functions. Here, authors provide structural insight into α_1AAR activation and binding modes of the orthosteric ligands and an extracellular allosteric nanobody.

  • Yosuke Toyoda
  • , Angqi Zhu
  •  & Xiangyu Liu

• Article
  07 June 2023 | Open Access

  Stabilization of pre-existing neurotensin receptor conformational states by β-arrestin-1 and the biased allosteric modulator ML314

  The authors highlight the importance of kinetics in GPCR activation. Using solution NMR, they show that the transducer βarrestin1 and the β-arrestin1biased ligand ML314 kinetically tune the conformational ensemble of the neurotensin receptor 1.

  • Fabian Bumbak
  • , James B. Bower
  •  & Joshua J. Ziarek

• Article
  06 June 2023 | Open Access

  Structural insights into ligand recognition and activation of the medium-chain fatty acid-sensing receptor GPR84

  The orphan GPR84 plays important roles in inflammation, fibrosis, and metabolism. Here, authors report cryo-EM structures of the receptor bound to two ligands, with insights into ligand binding and entry from the extracellular milieu.

  • Heng Liu
  • , Qing Zhang
  •  & Wanchao Yin

• Matters Arising
  01 June 2023 | Open Access

  The G protein preference of orexin receptors is currently an unresolved issue

  • Jyrki P. Kukkonen

• Matters Arising
  01 June 2023 | Open Access

  Reply to: The G protein preference of orexin receptors is currently an unresolved issue

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

• Article
  19 May 2023 | Open Access

  Computational design of dynamic receptor—peptide signaling complexes applied to chemotaxis

  Engineering protein biosensors that respond to biomolecules by triggering cellular responses has largely relied on binding rigid molecules. Here, the authors develop a computational strategy for designing signaling complexes between conformationally dynamic proteins and peptides.

  • Robert E. Jefferson
  • , Aurélien Oggier
  •  & Patrick Barth

• Article
  09 May 2023 | Open Access

  Structural basis for activation of CB1 by an endocannabinoid analog

  This manuscript describes the structure of an endocannabinoid analog-bound CB1 complex and reveals the structural determinants of ligand efficacy. The activation mechanism, unique to CB1, that is exploited by allosteric modulators is also outlined.

  • Kaavya Krishna Kumar
  • , Michael J. Robertson
  •  & Brian Kobilka

• Article
  09 May 2023 | Open Access

  Ligand-induced activation and G protein coupling of prostaglandin F_2α receptor

  Prostaglandin F_2α receptor (FP) is the primary therapeutic target for glaucoma and several other diseases. Here, the authors reveal structural mechanisms of ligand recognition, receptor activation, and G protein coupling by FP.

  • Canrong Wu
  • , Youwei Xu
  •  & H. Eric Xu

• Article
  28 April 2023 | Open Access

  A visual opsin from jellyfish enables precise temporal control of G protein signalling

  Jellyfish see light in a similar way that vertebrates smell odours. Here, Michiel van Wyk and Sonja Kleinlogel show how jellyfish has adapted this slow signal detection pathway to support sophisticated vision, and use a similar method to restore vision in blind mice.

  • Michiel van Wyk
  •  & Sonja Kleinlogel

• Article
  14 April 2023 | Open Access

  Constrained catecholamines gain β₂AR selectivity through allosteric effects on pocket dynamics

  Constrained catecholamines gain β₂AR selectivity. Although the orthosteric pockets are identical in β₁AR and β₂AR, surrounding residues allosterically modify the pockets and contribute to the β₂AR selectivity of the constrained catecholamines.

  • Xinyu Xu
  • , Jeremy Shonberg
  •  & Peter Gmeiner

• Article
  30 March 2023 | Open Access

  A Vaccinia-based system for directed evolution of GPCRs in mammalian cells

  G protein-coupled receptors are a major class of drug targets. Here, the authors develop a method whereby their biophysical and functional properties can be altered through directed evolution in mammalian cells, leading to variants exhibiting features such as high stability and expression, or increased allosteric coupling.

  • Christoph Klenk
  • , Maria Scrivens
  •  & Andreas Plückthun

• Article
  27 March 2023 | Open Access

  Structural insights into the human niacin receptor HCA2-G_i signalling complex

  Hydroxyl-carboxylic acid receptor 2 (HCA2) functions as a high-affinity receptor for nicotinic acid (vitamin B3). Here, authors report the cryo-EM structure of the HCA2-G_i complex with the agonist MK-6892 and inactive state crystal structures of mutation stabilized HCA2, to describe the mechanism of HCA2 signaling.

  • Yang Yang
  • , Hye Jin Kang
  •  & Zhi-Jie Liu

• Article
  11 March 2023 | Open Access

  Molecular mechanism of biased signaling at the kappa opioid receptor

  Biased signaling in κ-opiod receptors (KOR) offer an attractive strategy for pain management. Here the authors identify determinants of KOR signaling bias using structural methods in combination with molecular dynamics simulations.

  • Amal El Daibani
  • , Joseph M. Paggi
  •  & Tao Che

• Article
  10 March 2023 | Open Access

  Intermediate-state-trapped mutants pinpoint G protein-coupled receptor conformational allostery

  Understanding of GPCR activation is limited as the structural information fails to present the full spectrum of energy landscape. Here, authors establish a series of conformation-biased mutants that represent five conformational states lying along adenosine A_2A receptor (A_2AR) activation.

  • Xudong Wang
  • , Chris Neale
  •  & Libin Ye

• Article
  08 March 2023 | Open Access

  Two-step structural changes in M3 muscarinic receptor activation rely on the coupled G_q protein cycle

  During G_q protein activation, the separated Gα_q-GTP forms a stable complex with the ligand-activated hM3R and PLCβ. Here the authors demonstrate that a single M3 receptor FRET probe can display the real-time conformational dynamics of innate receptor by the downstream G_q protein cycle.

  • Yong-Seok Kim
  • , Jun-Hee Yeon
  •  & Byung-Chang Suh

• Article
  07 March 2023 | Open Access

  Structural basis of peptide recognition and activation of endothelin receptors

  Endothelin receptors (ETAR and ETBR) are critical for vasoregulation and are targets for cardiovascular diseases treatment. Here, the authors offer a structural basis for peptide recognition selectivity and activation of both endothelin receptors.

  • Yujie Ji
  • , Jia Duan
  •  & Yi Jiang

• Article
  01 March 2023 | Open Access

  Structural details of a Class B GPCR-arrestin complex revealed by genetically encoded crosslinkers in living cells

  The conformation of GPCR-arrestin complexes at the cell membrane, despite available structures, remains uncertain. This work reveals structure and dynamics of the PTH1R-arrestin2 complex, including flexible regions, in live cells.

  • Yasmin Aydin
  • , Thore Böttke
  •  & Irene Coin

• Article
  23 February 2023 | Open Access

  Structural basis of lysophosphatidylserine receptor GPR174 ligand recognition and activation

  GPR174 is a lysophosphatidylserine (LysoPS) activated GPCR. Here, the authors report the cryo-EM structure of LysoPS-bound human GPR174 in complex with G_s protein. The study reveals how GPR174 recognizes the lipid ligand and engages G_s in a distinct binding mode.

  • Jiale Liang
  • , Asuka Inoue
  •  & Yuanzheng He

• Article
  21 February 2023 | Open Access

  Prospect of acromegaly therapy: molecular mechanism of clinical drugs octreotide and paltusotine

  Somatostatin receptor 2 (SSTR2) represents a therapeutic target of neuroendocrine tumors. Here, authors report two structures of SSTR2 bound to peptide octreotide and small molecule paltusotine, revealing the basis subtype selectivity and signal bias properties.

  • Jie Zhao
  • , Hong Fu
  •  & Zhenhua Shao

• Article
  06 February 2023 | Open Access

  Isoform- and ligand-specific modulation of the adhesion GPCR ADGRL3/Latrophilin3 by a synthetic binder

  Adhesion GPCRs have numerous functions, ligands and isoforms. Here, Kordon et al. report synthetic antibodies that both modulate aGPCR signaling in an isoform-specific manner, and break receptor interactions in a ligand-specific manner

  • Szymon P. Kordon
  • , Przemysław Dutka
  •  & Demet Araç

• Article
  31 January 2023 | Open Access

  Mechanism of hormone and allosteric agonist mediated activation of follicle stimulating hormone receptor

  Follicle stimulating hormone (FSH) is a glycoprotein hormone the functions of which are mediated by a G protein-coupled receptor, FSHR. Here, Duan et al. report cryo-EM structures of FSHR in active and inactive states, suggesting the molecular basis of FSH and small allosteric agonist-mediated FSHR activation.

  • Jia Duan
  • , Peiyu Xu
  •  & H. Eric Xu

• Article
  30 January 2023 | Open Access

  Ligand recognition mechanism of the human relaxin family peptide receptor 4 (RXFP4)

  Relaxin family peptide receptor 4 (RXFP4) regulates pleiotropic biological processes. Here, authors report cryo-EM structures revealing the ligand-binding modes and key determinants of peptidomimetic agonism and subtype selectivity

  • Yan Chen
  • , Qingtong Zhou
  •  & Ming-Wei Wang