Featured
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| Open AccessProspect 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
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Article
| Open AccessIsoform- 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
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Article
| Open AccessMechanism 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
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Article
| Open AccessLigand 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
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Article
| Open AccessStructural and dynamic insights into supra-physiological activation and allosteric modulation of a muscarinic acetylcholine receptor
Here, using cryo-electron microscopy and solution NMR, the authors reveal the structural and dynamic mechanisms underlying the signaling versatility of a muscarinic receptor regulated by orthosteric and allosteric ligands.
- Jun Xu
- , Qinggong Wang
- & Brian K. Kobilka
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Article
| Open AccessRevealing the tissue-level complexity of endogenous glucagon-like peptide-1 receptor expression and signaling
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
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Article
| Open AccessThermodynamic architecture and conformational plasticity of GPCRs
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
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Article
| Open AccessLigand recognition and activation of neuromedin U receptor 2
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
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Article
| Open AccessDynamic spatiotemporal determinants modulate GPCR:G protein coupling selectivity and promiscuity
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
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Article
| Open AccessActivation and signaling mechanism revealed by GPR119-Gs complex structures
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
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Article
| Open AccessUnderstanding VPAC receptor family peptide binding and selectivity
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
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Article
| Open AccessStructure insights into selective coupling of G protein subtypes by a class B G protein-coupled receptor
Here, the authors report structures of corticotropin releasing factor receptor 2 (CRF2R) bound to agonist Urocortin 1 (UCN1) and coupled to G proteins G11 and Go, offering insight into the structural basis for the ability of CRF2R to couple with multiple G protein subtypes.
- Li-Hua Zhao
- , Jingyu Lin
- & H. Eric Xu
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Article
| Open AccessGPR97 triggers inflammatory processes in human neutrophils via a macromolecular complex upstream of PAR2 activation
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
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Article
| Open AccessBiased 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
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Article
| Open AccessMolecular insights into the distinct signaling duration for the peptide-induced PTH1R activation
Here the authors report two structures of human PTH1R-Gs complex bound to ligands PTH and ABL, providing insight into the molecular mechanism of ligand duration.
- Xiuwen Zhai
- , Chunyou Mao
- & Zhihong Liu
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Article
| Open AccessStructural basis for recognition of antihistamine drug by human histamine receptor
Crystal structure of human histamine receptor H3R bound to an antagonist PF-03654746 reveals the unexpected binding modes of the antagonist and allosteric cholesterol, which could facilitate the structure-based design of novel antihistamines.
- Xueqian Peng
- , Linlin Yang
- & Haitao Zhang
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Article
| Open AccessLocation bias contributes to functionally selective responses of biased CXCR3 agonists
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
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Article
| Open AccessStructural basis for recognition of N-formyl peptides as pathogen-associated molecular patterns
Detection of invading bacteria is key to immunity. Here, the authors report cryo-electron microscopy structures of agonist-bound formyl peptide receptor 1 (FPR1), that reveal structural basis for recognition of bacteria-derived formyl peptides.
- Geng Chen
- , Xiankun Wang
- & Richard D. Ye
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Article
| Open AccessStructural basis for receptor selectivity and inverse agonism in S1P5 receptors
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
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Article
| Open AccessAllosteric modulation of GPCR-induced β-arrestin trafficking and signaling by a synthetic intrabody
G protein-coupled receptors (GPCRs) are integral membrane proteins and the largest class of drug targets in the human genome. Here, Baidya et al. show that a synthetic antibody can be used to modulate GPCR trafficking and signaling in live cells.
- Mithu Baidya
- , Madhu Chaturvedi
- & Arun K. Shukla
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Article
| Open AccessG protein coupling and activation of the metabotropic GABAB heterodimer
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
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Article
| Open AccessFusion protein strategies for cryo-EM study of G protein-coupled receptors
Here, Zhang et al. explore fusion protein strategies to facilitate cryo-EM structural studies of GPCRs alone- without signal transducers- in ligand bound or unliganded form.
- Kaihua Zhang
- , Hao Wu
- & Yifan Cheng
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Article
| Open AccessStructural basis for the activation and ligand recognition of the human oxytocin receptor
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
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Article
| Open AccessStructures of β1-adrenergic receptor in complex with Gs and ligands of different efficacies
Su et al. report cryo-EM structures of β1-adrenergic receptor, Gs and ligands of different efficacies. These complexes have similar overall architecture, but with local conformational differences and different stabilities.
- Minfei Su
- , Navid Paknejad
- & Xin-Yun Huang
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Article
| Open AccessLigand recognition and biased agonism of the D1 dopamine receptor
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
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Article
| Open AccessMolecular 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
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Article
| Open AccessThe unconventional activation of the muscarinic acetylcholine receptor M4R by diverse ligands
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
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Article
| Open AccessThe 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
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Article
| Open AccessActivation and allosteric regulation of the orphan GPR88-Gi1 signaling complex
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
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Article
| Open AccessA distinctive ligand recognition mechanism by the human vasoactive intestinal polypeptide receptor 2
Vasoactive intestinal polypeptide receptor 2 (VIP2R) is involved in immunity. Here, the authors report two cryo-EM structures of the VIP2R–Gs in complex with the endogenous peptide ligand PACAP27, revealing a unique interaction mode between PACAP27 and the receptor, stabilized by the N-terminal α-helix of VIP2R.
- Yingna Xu
- , Wenbo Feng
- & Ming-Wei Wang
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Article
| Open AccessMechanism of sensitivity modulation in the calcium-sensing receptor via electrostatic tuning
Tuning of receptor sensitivity is often thought to rely on direct ligand-receptor interactions. Here, Schamber, et al. demonstrate the ability of a dimer interface to allosterically regulate calcium-sensing receptor (CaSR) sensitivity.
- Michael R. Schamber
- & Reza Vafabakhsh
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Article
| Open AccessStructural insights into the peptide selectivity and activation of human neuromedin U receptors
Neuromedin U receptors (NMURs) are potential drug targets for obesity and inflammatory disorders. Here, the authors report structural basis for neuromedin recognition and activation mechanism of NMURs.
- Chongzhao You
- , Yumu Zhang
- & Yi Jiang
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Article
| Open AccessExploration of the dynamic interplay between lipids and membrane proteins by hydrostatic pressure
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
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Article
| Open AccessStructural basis of FPR2 in recognition of Aβ42 and neuroprotection by humanin
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
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Article
| Open AccessStructural 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
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Article
| Open AccessStructural basis of neuropeptide Y signaling through Y1 receptor
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
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Article
| Open AccessCryo-EM structures of human bradykinin receptor-Gq 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
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Article
| Open AccessSchwann cell endosome CGRP signals elicit periorbital mechanical allodynia in mice
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
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Article
| Open AccessGPCR kinase knockout cells reveal the impact of individual GRKs on arrestin binding and GPCR regulation
GPCR kinases (GRKs) regulate GPCR interactions and thus functions. Here, the authors report a comprehensive panel of GRK knockout cells, used to assess the GRK-specific β-arrestin recruitment. Selective engagement of GRKs induces distinct GPCR–β-arrestin complexes.
- J. Drube
- , R. S. Haider
- & C. Hoffmann
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Article
| Open AccessHeterotrimeric Gq proteins act as a switch for GRK5/6 selectivity underlying β-arrestin transducer bias
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
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Article
| Open AccessStructural basis of the ligand binding and signaling mechanism of melatonin receptors
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
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Article
| Open AccessCrystal structure of the α1B-adrenergic receptor reveals molecular determinants of selective ligand recognition
This study reports the X-ray structure of the α1B-adrenergic G protein-coupled receptor bound to an inverse agonist, and unveils key determinants of subtype-selective ligand binding that may help the design of aminergic drugs with fewer side-effects.
- Mattia Deluigi
- , Lena Morstein
- & Andreas Plückthun
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Article
| Open AccessMolecular mechanism of agonism and inverse agonism in ghrelin receptor
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
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Article
| Open AccessDynamics 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
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Article
| Open AccessSingle molecule kinetics of bacteriorhodopsin by HS-AFM
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
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Article
| Open AccessBiphasic activation of β-arrestin 1 upon interaction with a GPCR revealed by methyl-TROSY NMR
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
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Article
| Open AccessStructure of the class C orphan GPCR GPR158 in complex with RGS7-Gβ5
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
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Article
| Open AccessAllosteric modulators enhance agonist efficacy by increasing the residence time of a GPCR in the active state
Here, the authors use smFRET to assess the structural dynamics of metabotropic glutamate receptor mGlu2 and show that a positive allosteric modulator or the Gi protein stabilize mGlu2 in the glutamate-induced active state, leading to the full activation of the receptor.
- Anne-Marinette Cao
- , Robert B. Quast
- & Emmanuel Margeat
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Article
| Open AccessGαq activation modulates autophagy by promoting mTORC1 signaling
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