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| Open AccessStructural basis for selectivity and antagonism in extracellular GPCR-nanobodies
Nanobodies are promising GPCR-targeting therapeutics. Here, the authors investigate a nanobody targeting atypical chemokine receptor 3 (ACKR3), and map trends in GPCR nanobody structure, mechanism, and selectivity.
- Roman R. Schlimgen
- , Francis C. Peterson
- & Brian F. Volkman
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Article
| Open AccessG protein-specific mechanisms in the serotonin 5-HT2A receptor regulate psychosis-related effects and memory deficits
Here authors aim to understand the 5-HT2AR coupling signature in response to different signaling probes and their physiological impacts using computational modeling, in vitro and in vivo experiments, and analysis of human brain tissue.
- Elk Kossatz
- , Rebeca Diez-Alarcia
- & Jana Selent
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Article
| Open AccessImpact of secretin receptor homo-dimerization on natural ligand binding
GPCRs can form functionally important dimers. Here, authors study impact of dimerization of the secretin receptor on peptide ligand binding and show high receptor conformational dynamics that facilitate G protein recruitment and activation.
- Kaleeckal G. Harikumar
- , Sarah J. Piper
- & Laurence J. Miller
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Article
| Open AccessStructural and dynamic insights into the activation of the μ-opioid receptor by an allosteric modulator
Here, the authors utilise NMR and cryo-EM to characterise the binding of an allosteric modulator to μ-opioid receptor (MOR), revealing modulator binding can potentiate receptor activation by altering the conformational dynamics in the core region of MOR.
- Shun Kaneko
- , Shunsuke Imai
- & Ichio Shimada
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Article
| Open AccessStructural 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
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Article
| Open AccessSpecific pharmacological and Gi/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
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Article
| Open AccessStructure-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
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Article
| Open AccessCryo-EM structure of cell-free synthesized human histamine 2 receptor/Gs complex in nanodisc environment
The study describes the molecular structure of the human histamine 2 receptor in active conformation and in complex with Gs heterotrimer, synthesized in a cell-free system and co-translationally inserted into preformed nanodiscs.
- Zoe Köck
- , Kilian Schnelle
- & Frank Bernhard
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Article
| Open AccessBinding 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
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Article
| Open AccessStructural 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
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Article
| Open AccessMolecular 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
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Article
| Open AccessMolecular 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
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Article
| Open AccessUnravelling 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
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Article
| Open AccessStructures of human prostaglandin F2α 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 F2α receptor, providing guidance for development of better postpartum hemorrhage drugs.
- Xiuqing Lv
- , Kaixuan Gao
- & Xiangyu Liu
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Article
| Open AccessStructural 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
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Matters Arising
| Open AccessReply to: How carvedilol does not activate β2-adrenoceptors
- Evi Kostenis
- , Jesus Gomeza
- & Stefan Schulz
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Article
| Open AccessDistinct 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
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Article
| Open AccessOrthosteric 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
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Article
| Open AccessStructural 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
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Article
| Open AccessStructural 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
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Article
| Open AccessStructural 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
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Article
| Open AccessGLP-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
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Article
| Open AccessAn 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
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Article
| Open AccessStructural 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
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Article
| Open AccessSpecific binding of GPR174 by endogenous lysophosphatidylserine leads to high constitutive Gs 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
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Article
| Open AccessStructural 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
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Article
| Open AccessLigand 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
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Article
| Open AccessMolecular 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
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Article
| Open AccessMembrane 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
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Article
| Open AccessGPCRome-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
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Article
| Open AccessStructural 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
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Article
| Open AccessProfiling 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
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Article
| Open AccessStructural basis of α1A-adrenergic receptor activation and recognition by an extracellular nanobody
α1A-adrenergic receptor (α1AAR) regulates smooth muscle contraction and cognitive functions. Here, authors provide structural insight into α1AAR activation and binding modes of the orthosteric ligands and an extracellular allosteric nanobody.
- Yosuke Toyoda
- , Angqi Zhu
- & Xiangyu Liu
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Article
| Open AccessStabilization 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
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Article
| Open AccessStructural 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
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Matters Arising
| Open AccessThe G protein preference of orexin receptors is currently an unresolved issue
- Jyrki P. Kukkonen
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Matters Arising
| Open AccessReply to: The G protein preference of orexin receptors is currently an unresolved issue
- Jie Yin
- , Yanyong Kang
- & Daniel M. Rosenbaum
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Article
| Open AccessComputational 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
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Article
| Open AccessStructural 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
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Article
| Open AccessLigand-induced activation and G protein coupling of prostaglandin F2α receptor
Prostaglandin F2α 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
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Article
| Open AccessA 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
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Article
| Open AccessConstrained 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
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Article
| Open AccessA 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
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Article
| Open AccessStructural insights into the human niacin receptor HCA2-Gi 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-Gi 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
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Article
| Open AccessMolecular 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
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Article
| Open AccessIntermediate-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 A2A receptor (A2AR) activation.
- Xudong Wang
- , Chris Neale
- & Libin Ye
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Article
| Open AccessTwo-step structural changes in M3 muscarinic receptor activation rely on the coupled Gq protein cycle
During Gq protein activation, the separated Gαq-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 Gq protein cycle.
- Yong-Seok Kim
- , Jun-Hee Yeon
- & Byung-Chang Suh
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Article
| Open AccessStructural 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
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Article
| Open AccessStructural 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