Receptor pharmacology articles within Nature Communications

Featured

• 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
  10 January 2024 | Open Access

  Ligand coupling mechanism of the human serotonin transporter differentiates substrates from inhibitors

  The serotonin transporter, targeted by several medications, terminates neurotransmission by clearing serotonin from the synaptic cleft. Combining biochemical results with in silico data, the authors show the key interactions that initiate substrate transport.

  • Ralph Gradisch
  • , Katharina Schlögl
  •  & Thomas Stockner

• Article
  15 December 2023 | Open Access

  Identification of 5-HT_2A receptor signaling pathways associated with psychedelic potential

  Serotonin 5-HT_2A receptor signaling mechanisms associated with predicting psychedelic potential remain elusive. Using 5-HT_2A-selective β-arrestin-biased ligands, here the authors show that a threshold level of 5-HT_2A-Gq efficacy and not β-arrestin recruitment is associated with psychedelic potential.

  • Jason Wallach
  • , Andrew B. Cao
  •  & John D. McCorvy

• Article
  06 December 2023 | Open Access

  Design and structural validation of peptide–drug conjugate ligands of the kappa-opioid receptor

  Despite advances in GPCR structures and peptide design, creating high-affinity ligands remains a challenge. Here the authors develop a computational method, successfully identifying peptide-based molecules for KOR: their platform shows promise for streamlined GPCR ligand discovery.

  • Edin Muratspahić
  • , Kristine Deibler
  •  & Christian W. Gruber

• 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
  06 September 2023 | Open Access

  Xanomeline displays concomitant orthosteric and allosteric binding modes at the M₄ mAChR

  The drug Xanomeline is progressing through clinical trials for the treatment of patients with schizophrenia. Here, the authors determine a cryo-EM structure of Xanomeline bound to its primary target revealing a dual binding mode mechanism.

  • Wessel A. C. Burger
  • , Vi Pham
  •  & David M. Thal

• Article
  10 August 2023 | Open Access

  Structural basis of agonist specificity of α_1A-adrenergic receptor

  α1-adrenergic receptors (α1- AR) play critical roles in the cardiovascular and nervous systems. Here, the authors report molecular insights into the mechanisms underlying the discrimination between α1A-AR and α1B-AR by the agonist A61603.

  • Minfei Su
  • , Jinan Wang
  •  & Xin-Yun Huang

• Article
  29 July 2023 | Open Access

  Pathway selectivity in Frizzleds is achieved by conserved micro-switches defining pathway-determining, active conformations

  Signaling pathway selectivity downstream of GPCRs is not fully understood. Here, authors perform functional analysis of Frizzled mutants to uncover state-stabilizing residues or ‘micro-switches’ mediating selectivity towards Disheveled over G proteins.

  • Lukas Grätz
  • , Maria Kowalski-Jahn
  •  & Gunnar Schulte

• 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
  08 June 2023 | Open Access

  Pregnane X receptor agonist nomilin extends lifespan and healthspan in preclinical models through detoxification functions

  The increase in detoxification gene expression is a common transcriptome marker for longevity interventions. Here, the authors show that nomilin extends lifespan and healthspan in animals through activation of PXR regulated detoxification functions.

  • Shengjie Fan
  • , Yingxuan Yan
  •  & Cheng Huang

• 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

  Characterisation of IL-23 receptor antagonists and disease relevant mutants using fluorescent probes

  The single nucleotide polymorphism C115Y in the IL-23 receptor is associated with autoinflammatory diseases. Here the authors demonstrate that this mutation prevents the binding of a fluorescent cyclic peptide and IL-23 to the IL-23 receptor.

  • Charles S. Lay
  • , Albert Isidro-Llobet
  •  & Stephen J. Hill

• Article
  11 May 2023 | Open Access

  Monoterpenoid aryl hydrocarbon receptor allosteric antagonists protect against ultraviolet skin damage in female mice

  The aryl hydrocarbon receptor regulates the expression of genes involved in many cell processes and its dysregulation has been implicated in different diseases. Here, the authors identify dietary monoterpenoid carvone as an atypical non-competitive antagonist of human aryl hydrocarbon receptor and demonstrate that it can protect against ultraviolet skin damage in female mice.

  • Karolína Ondrová
  • , Iveta Zůvalová
  •  & Zdeněk Dvořák

• Article
  15 March 2023 | Open Access

  Structural basis of selective cannabinoid CB₂ receptor activation

  Cannabinoid CB₂ receptor (CB₂R) agonists are investigated as therapeutic agents in the clinic. Here, authors report the discovery of LEI-102, a CB₂R agonist, used in conjunction with three other CBR ligands (APD371, HU308, and CP55,940) to investigate selective CB₂R activation.

  • Xiaoting Li
  • , Hao Chang
  •  & Tian Hua

• 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

• Article
  03 January 2023 | Open Access

  Structure-guided peptide engineering of a positive allosteric modulator targeting the outer pore of TRPV1 for long-lasting analgesia

  TRPV1 as a drug target suffers from side effects of hypothermia. Here, authors engineer a peptide, sRhTx, as a positive allosteric modulator of TRPV1 channel. It potentiates the activity of TRPV1 to reversibly ablate pain-sensing nerve terminals for long-lasting analgesia without changing mice body temperature.

  • Heng Zhang
  • , Jia-Jia Lin
  •  & Fan Yang

• Article
  21 November 2022 | Open Access

  Structural basis of synthetic agonist activation of the nuclear receptor REV-ERB

  The nuclear receptor REV-ERBα is a receptor for heme and plays a role in a range of physiological processes. Here, the authors provide the first structure of REV-ERB bound to a synthetic nonporphyrin ligand defining key mechanistic differences to how heme binds.

  • Meghan H. Murray
  • , Aurore Cecile Valfort
  •  & Thomas P. Burris

• Article
  19 November 2022 | Open Access

  How Carvedilol activates β₂-adrenoceptors

  How carvedilol, a β1-blocker, activates β2-adrenoceptors, is unclear. Here, the authors resolve this enigma and show that carvedilol drives all of its detectable cellular β2-adrenoceptor signals by slow and low efficacy G protein activation.

  • Tobias Benkel
  • , Mirjam Zimmermann
  •  & Evi Kostenis

• Article
  26 October 2022 | Open Access

  Biased signaling due to oligomerization of the G protein-coupled platelet-activating factor receptor

  The functional consequence of G protein-coupled receptor oligomerization remains debated. Here the authors show that platelet-activating factor receptor oligomerization enhances G protein coupling, and restrains β-arrestin recruitment and internalization.

  • Junke Liu
  • , Hengmin Tang
  •  & Jianfeng Liu

• Article
  06 August 2022 | Open Access

  Structural and dynamic mechanisms of GABA_A receptor modulators with opposing activities

  GABA_A receptors are important targets for anxiety, sedation and anesthesia. Here, the authors present structures bound by zolpidem (Ambien), the most prescribed hypnotic in the US, and DMCM, a negative modulator, providing insights into receptor modulation.

  • Shaotong Zhu
  • , Akshay Sridhar
  •  & Ryan E. Hibbs

• Article
  18 July 2022 | Open Access

  Selective activation of Gαob by an adenosine A₁ receptor agonist elicits analgesia without cardiorespiratory depression

  Wall et al. describe the selective activation of an adenosine A1 receptor-mediated intracellular pathway that provides potent analgesia in the absence of sedation or cardiorespiratory depression, paving the way for novel medicines based on the far-reaching concept of selective Gα agonism.

  • Mark J. Wall
  • , Emily Hill
  •  & Bruno G. Frenguelli

• Comment
  15 July 2022 | Open Access

  Timing is everything: structural insights into the disease-linked Kv3 channels controlling fast action-potential firing in the brain

  Kv3 channels enable neurons to fire at very high frequencies (>100 Hz) which is fundamental to brain development and our ability to make sense of the world at large. Cryo-EM and structure-function studies by Chi et al. now uncover Kv3 channel gating mechanisms and support new precision medicine approaches for CNS diseases.

  • Martin J. Gunthorpe

• Article
  15 July 2022 | Open Access

  Inhibition of NMDA receptors through a membrane-to-channel path

  Wilcox et al. (2022) show that NMDA receptor channel blockers, some of which are clinically important drugs, can access their binding site via 2 routes: a well-known path from the extracellular solution, and another path through the plasma membrane.

  • Madeleine R. Wilcox
  • , Aparna Nigam
  •  & Jon W. Johnson

• Article
  16 June 2022 | Open Access

  Coordination chemogenetics for activation of GPCR-type glutamate receptors in brain tissue

  Cell-type-specific activation of receptors is desirable for elucidating their roles in tissues or animals. Here, the authors developed a chemogenetic method for direct activation of mGlu1, a GPCR-type glutamate receptor subtype, and demonstrate its use in mouse brain tissue.

  • Kento Ojima
  • , Wataru Kakegawa
  •  & Shigeki Kiyonaka

• Article
  25 May 2022 | Open Access

  Molecular mechanism of the wake-promoting agent TAK-925

  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
  10 May 2022 | Open Access

  The pocketome of G-protein-coupled receptors reveals previously untargeted allosteric sites

  G-protein-coupled receptors bind endogenous ligands at sites that are frequently highly conserved. Here, authors computationally describe alternative allosteric pockets, several of which have not been targeted by synthetic ligands before.

  • Janik B. Hedderich
  • , Margherita Persechino
  •  & Peter Kolb

• Article
  25 February 2022 | Open Access

  Structural insights into multiplexed pharmacological actions of tirzepatide and peptide 20 at the GIP, GLP-1 or glucagon receptors

  Multi-targeting agonists at GIPR, GLP-1R or GCGR are pursued vigorously. Here, the authors report cryo-EM structures of tirzepatide-bound GIPR and GLP-1R, peptide 20-bound GIPR, GLP-1R and GCGR, revealing the molecular basis of their multiplexed pharmacological actions.

  • Fenghui Zhao
  • , Qingtong Zhou
  •  & Ming-Wei Wang

• Article
  17 February 2022 | Open Access

  Functionally selective signaling and broad metabolic benefits by novel insulin receptor partial agonists

  Insulin therapies for patients with diabetes have challenges, including diminished hepatic preference of insulin action compared with endogenous insulin. Here the authors characterize insulin dimers that function as insulin receptor partial agonists, and exhibit hepatic and adipose tissue preference of insulin action and metabolic benefits in preclinical models.

  • Margaret Wu
  • , Ester Carballo-Jane
  •  & James Mu

• Article
  07 February 2022 | Open Access

  Cryo-EM structures of human bradykinin receptor-G_q proteins complexes

  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
  10 January 2022 | Open Access

  Dynamics of GLP-1R peptide agonist engagement are correlated with kinetics of G protein activation

  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
  16 July 2021 | Open Access

  Selective targeting of ligand-dependent and -independent signaling by GPCR conformation-specific anti-US28 intrabodies

  Various GPCRs display constitutive ligand-independent activity, but it remains unclear whether ligand-dependent and -independent conformations differ. Here the authors demonstrate the recognition and blocking of G protein recruitment of either the ligand-bound active, or the constitutively active apo-conformation of the viral GPCR US28 by different nanobodies that target similar intracellular loops of the receptor.

  • Timo W. M. De Groof
  • , Nick D. Bergkamp
  •  & Martine J. Smit

• Article
  15 July 2021 | Open Access

  Routine sub-2.5 Å cryo-EM structure determination of GPCRs

  There is a need to optimise cryo-EM data acquisition approaches to improve the resolution of GPCR cryo-EM structures to better than 2.5 Å, in order to use them for structure-based drug design purposes. Here, the authors present a systematic analysis of the main cryo-EM experimental parameters using three GPCRs as test cases, which is also of interest for the cryo-EM structure determination of other small membrane proteins.

  • Radostin Danev
  • , Matthew Belousoff
  •  & Patrick M. Sexton

• Article
  22 June 2021 | Open Access

  Site selective C–H functionalization of Mitragyna alkaloids reveals a molecular switch for tuning opioid receptor signaling efficacy

  Mitragynine (MG) is an indole alkaloid from kratom plant that binds opioid receptors and as such presents a scaffold for the development of atypical opioid receptor modulators. Here, the authors report a synthetic method for selective functionalization of the C11 position of MG, and show that this position is essential for fine-tuning opioid receptor signaling efficacy.

  • Srijita Bhowmik
  • , Juraj Galeta
  •  & Dalibor Sames

• Article
  18 June 2021 | Open Access

  Molecular insights into ago-allosteric modulation of the human glucagon-like peptide-1 receptor

  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 G_s which offers insights into the molecular details of ago-allosterism.

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

• Article
  03 June 2021 | Open Access

  Crystal structure of dopamine D1 receptor in complex with G protein and a non-catechol agonist

  Recently, a class of non-catechol Dopamine D1 receptor (D1R) selective agonists with novel scaffold and improved pharmacological properties were reported. Here, authors report the crystal structure of D1R in complex with stimulatory G protein (Gs) and a non-catechol agonist Compound 1 which explains the selectivity of this scaffold for D1R over other aminergic receptors and the mechanism of activating D1R.

  • Bingfa Sun
  • , Dan Feng
  •  & Brian K. Kobilka

• Article
  02 February 2021 | Open Access

  Structural basis for ligand recognition of the neuropeptide Y Y₂ receptor

  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
  21 September 2020 | Open Access

  GPR101 drives growth hormone hypersecretion and gigantism in mice via constitutive activation of G_s and G_q/11

  Growth hormone (GH) is a major modulator of physical growth and metabolism that is under tight regulatory control. Here the authors describe the signaling profile of GPR101, an orphan receptor that enhances GH secretion principally via constitutively activated Gs-PKA and Gq/11-PKC pathways.

  • Dayana Abboud
  • , Adrian F. Daly
  •  & Julien Hanson

• Article
  29 April 2020 | Open Access

  Improved GPCR ligands from nanobody tethering

  Antibodies conjugated to bioactive compounds can allow targeted delivery of therapeutics. Here the authors present a strategy for fusing nanobodies to suboptimal GPCR peptide ligands to potently and selectively activate receptors.

  • Ross W. Cheloha
  • , Fabian A. Fischer
  •  & Hidde L. Ploegh

• Article
  26 February 2020 | Open Access

  Haloperidol bound D₂ dopamine receptor structure inspired the discovery of subtype selective ligands

  The D₂ dopamine receptor (DRD2) is one of the most well-established therapeutic targets for neuropsychiatric and endocrine disorders. Here, the authors report the crystal structure of the antipsychotic drug haloperidol bound to DRD2 via an extended binding pocket that distinguishes it from other D₂-like subtypes.

  • Luyu Fan
  • , Liang Tan
  •  & Sheng Wang

• Article
  23 January 2020 | Open Access

  Chaperone mediated detection of small molecule target binding in cells

  Quantitative profiling of small molecule-protein binding in cells can aid basic biochemical research and drug discovery. Here, the authors develop the Heat Shock Protein Inhibition Protein Stability Assay (HIPStA) as a high-throughput method to assess cellular target engagement and identify new drug targets.

  • Kelvin F. Cho
  • , Taylur P. Ma
  •  & Robert A. Blake

• Article
  21 January 2020 | Open Access

  Structural insight into small molecule action on Frizzleds

  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
  03 October 2019 | Open Access

  A mechanism for the activation of the mechanosensitive Piezo1 channel by the small molecule Yoda1

  Besides mechanical forces, the mechanosensitive channel Piezo1 is activated by the small molecule Yoda1 through an unknown mechanism. Here, using molecular dynamics simulations, calcium imaging and electrophysiology, the authors identify an allosteric Yoda1 binding pocket located in the putative mechanosensory domain.

  • Wesley M. Botello-Smith
  • , Wenjuan Jiang
  •  & Yun Luo

• Article
  23 July 2019 | Open Access

  Cryptic pocket formation underlies allosteric modulator selectivity at muscarinic GPCRs

  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
  08 February 2019 | Open Access

  A conserved molecular switch in Class F receptors regulates receptor activation and pathway selection

  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
  21 January 2019 | Open Access

  Phosphorylation-deficient G-protein-biased μ-opioid receptors improve analgesia and diminish tolerance but worsen opioid side effects

  Tolerance and other side effects are important limitations to the use of opioids as analgesics. In this study, the authors generated mice lacking phosphorylation sites on the µ-opioid receptor to assess their contribution to the analgesic, tolerance and side effect profile of opioid analgesics.

  • A. Kliewer
  • , F. Schmiedel
  •  & S. Schulz

• Correspondence
  03 September 2018 | Open Access

  Reply to ‘Antipsychotics with similar association kinetics at dopamine D₂ receptors differ in extrapyramidal side-effects’

  • David A. Sykes
  • , J. Robert Lane
  •  & Steven J. Charlton

• Correspondence
  03 September 2018 | Open Access

  Antipsychotics with similar association kinetics at dopamine D₂ receptors differ in extrapyramidal side-effects

  • Hugo Zeberg
  •  & Kristoffer Sahlholm

• Article
  23 July 2018 | Open Access

  The conformational wave in capsaicin activation of transient receptor potential vanilloid 1 ion channel

  The capsaicin receptor TRPV1 has been structurally characterized, but the capsaicin activation dynamics remain elusive. Here authors use fluorescent unnatural amino acid incorporation, computational modeling and Φ-analysis to derive the capsaicin-bound open state model and reveal the capsaicin induced conformational changes.

  • Fan Yang
  • , Xian Xiao
  •  & Jie Zheng

• Article
  17 May 2018 | Open Access

  A novel small molecule chaperone of rod opsin and its potential therapy for retinal degeneration

  Mutations that lead to misfolding of rhodopsin can cause retinitis pigmentosa. Here, the authors carry out a high throughput screen to identify a small molecule chaperone of rod opsin, and show that it protects mouse models of retinitis pigmentosa from retinal degeneration.

  • Yuanyuan Chen
  • , Yu Chen
  •  & Krzysztof Palczewski

• Article
  04 May 2018 | Open Access

  Defining a conformational ensemble that directs activation of PPARγ

  Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor. Here the authors provide insights into PPARγ activation by combining fluorine (¹⁹F) NMR and molecular dynamics simulations to characterize the nuclear receptor conformational ensemble in solution and the response of this ensemble to ligand and coregulatory peptide binding.

  • Ian M. Chrisman
  • , Michelle D. Nemetchek
  •  & Travis S. Hughes