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| Open AccessKisspeptin-10 binding to Gpr54 in osteoclasts prevents bone loss by activating Dusp18-mediated dephosphorylation of Src
The authors of this manuscript identify that Gpr54 activation by its natural ligand Kisspeptin-10 can abrogate bone resorption. Mechanistically, Gpr54 recruits both active Src and the Dusp18 phosphatase, which causes Dusp18 to dephosphorylate Src at Tyr 416.
- Zhenxi Li
- , Xinghai Yang
- & Jianru Xiao
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Article
| Open AccessAndrogen drives melanoma invasiveness and metastatic spread by inducing tumorigenic fucosylation
Mechanisms underlying sex associated differences in the role of androgen receptor (AR) in melanoma are unclear. Here the authors show that androgen-activated AR transcriptionally upregulates fucosyltransferase 4, which fucosylates L1CAM and promotes melanoma invasiveness by disrupting adherens junctions.
- Qian Liu
- , Emma Adhikari
- & Eric K. Lau
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Article
| Open AccessAndrogen receptor is a determinant of melanoma targeted drug resistance
BRAF inhibitor response in melanoma is variable, and BRAF mutated patients often relapse. Here, the authors show that androgen receptor expression is linked to BRAF inhibitor response, and is a potential therapeutic target to increase efficacy.
- Anastasia Samarkina
- , Markus Kirolos Youssef
- & Gian Paolo Dotto
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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 AccessLoss of LCMT1 and biased protein phosphatase 2A heterotrimerization drive prostate cancer progression and therapy resistance
Loss of PP2A activity is often associated with cancer but the underlying mechanism remains unclear. Here, the authors show that decreased methylation of PP2A catalytic C subunit caused by loss of LCMT-1 in prostate cancer abrogates the tumor suppressor activity of PP2A on AR/MED1-dependent gene expression, proposing decreased methyl-PP2A-C as a prognostic marker for prostate cancer progression.
- Reyaz ur Rasool
- , Caitlin M. O’Connor
- & Irfan A. Asangani
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Article
| Open AccessMacrophage-to-endothelial cell crosstalk by the cholesterol metabolite 27HC promotes atherosclerosis in male mice
Hypercholesterolemia and vascular inflammation both contribute to the pathogenesis of atherosclerosis, but how hypercholesterolemia initiates vascular inflammation is not fully understood. Here the authors report that crosstalk between macrophages and endothelial cells mediated by the cholesterol metabolite 27-hydroxycholesterol drives vascular inflammation and contributes to atherosclerosis in male mice.
- Liming Yu
- , Lin Xu
- & Philip W. Shaul
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Article
| Open AccessStructural 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 Gs protein. The study reveals how GPR174 recognizes the lipid ligand and engages Gs in a distinct binding mode.
- Jiale Liang
- , Asuka Inoue
- & Yuanzheng He
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Article
| Open AccessHyperaminoacidemia induces pancreatic α cell proliferation via synergism between the mTORC1 and CaSR-Gq signaling pathways
Insufficient glucagon signalling results in hyperaminoacidemia, which drives adaptive proliferation of glucagon-producing α cells. Here the authors report that the amino acid sensitive calcium sensing receptor (CaSR) is necessary for α cell proliferation via Gq signalling during hyperaminoacidemia.
- Yulong Gong
- , Bingyuan Yang
- & Wenbiao Chen
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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 AccessGi/o protein-coupled receptor inhibition of beta-cell electrical excitability and insulin secretion depends on Na+/K+ ATPase activation
Gi/o protein-coupled receptors (Gi/o-GPCRs) limit β-cell insulin secretion by decreasing Ca2+ entry; however, the underlying mechanism has not been identified. Here, the authors show that Gi/o-GPCRs hyperpolarize mouse and human β-cell membrane potential by activating Na+/K+ATPases.
- Matthew T. Dickerson
- , Prasanna K. Dadi
- & David A. Jacobson
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Article
| Open AccessStructural basis of adhesion GPCR GPR110 activation by stalk peptide and G-proteins coupling
aGPCRs play key roles in multiple physiological processes. Here the authors report cryo-EM structures of GPR110 in complexes with Gq, Gs, Gi, G12 and G13 protein to reveal a detailed mechanism of aGPCR activation via the tethered stalk peptide and principles of G-protein coupling and selectivity on GPR110.
- Xinyan Zhu
- , Yu Qian
- & Yuanzheng He
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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 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 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 AccessKinetic model of GPCR-G protein interactions reveals allokairic modulation of signaling
Experimentally validated kinetic simulations uncover transient enhancement of GPCR ternary complex formation by allokairic effectors.
- Kelly J. Culhane
- , Tejas M. Gupte
- & Sivaraj Sivaramakrishnan
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Article
| Open AccessStructural basis of leukotriene B4 receptor 1 activation
In the paper, Dr. Wang et al reported a cryo-EM structure of the human leukotriene B4 receptor 1 (BLT1) in complex with its native ligand leukotriene B4 (LTB4) in an active conformation complexed with Gi protein. The structure reveals the molecule determinant of LTB4 binding and the mechanism of receptor activation. These structural information will boost the understanding of LTB4-BLT1 signaling and provide a rational basis for designing novel anti-leukotriene drugs.
- Na Wang
- , Xinheng He
- & Yuanzheng He
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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 human ghrelin receptor signaling by ghrelin and the synthetic agonist ibutamoren
Ghrelin is a central orexigenic peptide hormone in human energy homeostasis that is also known as ‘hunger hormone’ and signals through its GPCR, GHSR. Here, the authors present the cryo-EM structures of the human GHSR-Gi signaling complex with bound ghrelin and the synthetic non-peptide agonist ibutamoren that are of interest for drug design.
- Heng Liu
- , Dapeng Sun
- & Cheng Zhang
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Article
| Open AccessA nutrient-responsive hormonal circuit mediates an inter-tissue program regulating metabolic homeostasis in adult Drosophila
Maintaining metabolic homeostasis during feeding and fasting states is critical to animal survival. Here the authors show that Capa hormone signaling, homologs to mammalian Neuromedin U, helps control homeostasis via regulation of nutrient uptake and energy storage in Drosophila.
- Takashi Koyama
- , Selim Terhzaz
- & Kenneth V. Halberg
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Article
| Open AccessDiscovery of a dual Ras and ARF6 inhibitor from a GPCR endocytosis screen
While Ras is a promising target for cancer therapy, development of inhibitors targeting Ras signaling has proven challenging. Here, the authors report the discovery of Rasarfin, a small molecule from a phenotypic screen on G protein-coupled receptor (GPCR) endocytosis that acts as a dual Ras and ARF6 inhibitor.
- Jenna Giubilaro
- , Doris A. Schuetz
- & Stéphane A. Laporte
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Article
| Open AccessCryo-EM structure of the human histamine H1 receptor/Gq complex
Histamine receptors are effective targets for allergy treatments and antihistamines are the first choice of many allergic disorders, but the exact mechanism of agonist binding and receptor activation remain unknown. Here, the authors present the cryo-EM structure of histamine-bound H1R/Gq complex and propose a mechanism of ligand induced receptor activation.
- Ruixue Xia
- , Na Wang
- & Yuanzheng He
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Article
| Open AccessGenome-wide binding potential and regulatory activity of the glucocorticoid receptor’s monomeric and dimeric forms
Glucocorticoid receptors (GR) are thought to bind DNA as dimers or monomers, to regulate different transcription pathways. Here, the authors perform genome-wide studies on GRs with mutations that impair dimerization and provide evidence that monomeric GRs do not play a significant physiologic role.
- Thomas A. Johnson
- , Ville Paakinaho
- & Diego M. Presman
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Article
| Open AccessGPR101 drives growth hormone hypersecretion and gigantism in mice via constitutive activation of Gs and Gq/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
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Article
| Open AccessCytokinin fluoroprobe reveals multiple sites of cytokinin perception at plasma membrane and endoplasmic reticulum
Cytokinin receptors predominantly localize to the endoplasmic reticulum. Here, Kubiasová et al. use a cytokinin fluoroprobe to show that ER-localized cytokinin receptors can enter the secretory pathway, reach the plasma membrane and undergo vesicular recycling, suggesting multiple sites of cytokinin perception.
- Karolina Kubiasová
- , Juan Carlos Montesinos
- & Lukáš Spíchal
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Article
| Open AccessRXRs control serous macrophage neonatal expansion and identity and contribute to ovarian cancer progression
Macrophages can differentiate to perform homeostatic tissue-specific functions. Here the authors show that RXR signalling is critical for large peritoneal macrophage (LPM) expansion during neonatal life and LPM lipid metabolism and survival during adult homeostasis, and that ovarian cancer growth relies on RXR-dependent LPMs.
- María Casanova-Acebes
- , María Piedad Menéndez-Gutiérrez
- & Mercedes Ricote
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Article
| Open AccessAndrogen receptor-binding sites are highly mutated in prostate cancer
Androgen receptor (AR) mediated transcription is critical to prostate tumorigenesis and development. Here, utilising clinical whole genome sequencing data, the authors show that the non-coding AR binding sites on DNA are frequently mutated in prostate cancer potentially due to faulty base excision repair mechanisms
- Tunç Morova
- , Daniel R. McNeill
- & Nathan A. Lack
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Article
| Open AccessTherapeutic senescence via GPCR activation in synovial fibroblasts facilitates resolution of arthritis
Fibroblast hyper-activation and proliferation is a major feature in arthritis, yet scarcely addressed for anti-arthritic therapies. Here, the authors show that activation of the MC1 receptor induces fibroblast senescence associated with a reparative phenotype, ultimately regulating experimental inflammatory arthritis.
- Trinidad Montero-Melendez
- , Ai Nagano
- & Mauro Perretti
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Article
| Open AccessMinute-scale persistence of a GPCR conformation state triggered by non-cognate G protein interactions primes signaling
Recent reports suggest the spatial and temporal coupling of receptor-effector interactions, with the potential to diversify downstream responses. Here authors demonstrate the temporal coupling of cognate and non-cognate G protein interactions through priming of GPCR conformation.
- Tejas M. Gupte
- , Michael Ritt
- & Sivaraj Sivaramakrishnan
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Article
| Open AccessLocal membrane charge regulates β2 adrenergic receptor coupling to Gi3
In the healthy heart, the β2 adrenergic receptor (β2AR) signals through Gs and Gi proteins but the mechanism underlying G protein selectivity is not fully understood. Here, the authors show that membrane charge and intracellular cations modulate the β2AR−Gi3 interaction.
- M. J. Strohman
- , S. Maeda
- & B. K. Kobilka
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Article
| Open AccessTamoxifen therapy in a murine model of myotubular myopathy
Myotubular myopathy is a severe muscle disease for which no effective treatment exists. Here, the authors show that tamoxifen ameliorates pathology and extends survival in a mouse model of the disease, and that the effect is mediated via estrogen receptor signaling and involves modulation of DNM2 expression.
- Nika Maani
- , Nesrin Sabha
- & James J. Dowling
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Article
| Open AccessCrystal structures of human ETB receptor provide mechanistic insight into receptor activation and partial activation
Signalling through the endothelin receptor ETB, a class A GPCR, induces nitric oxide-mediated vasorelaxation. Here the authors present the crystal structures of the human ETB receptor bound to the peptide hormone endothelin-3 and in complex with the ETB-selective partial agonist IRL1620 and discuss mechanistic implications for receptor activation.
- Wataru Shihoya
- , Tamaki Izume
- & Osamu Nureki
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Article
| Open AccessHomocysteine directly interacts and activates the angiotensin II type I receptor to aggravate vascular injury
High homocysteine plasma levels are associated with cardiovascular diseases. Here, Li and colleagues find that homocysteine aggravates vascular injury by direct binding to the angiotensin II type 1 receptor (AT1R), identifying AT1R inhibition as a potential strategy to counteract the deleterious vascular effects of hyperhomocysteinemia.
- Tuoyi Li
- , Bing Yu
- & Wei Kong
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Article
| Open AccessDiscovery of naturally occurring ESR1 mutations in breast cancer cell lines modelling endocrine resistance
ESR1 mutations occur in endocrine-resistant patients but have not yet been reported in in vitro models of breast cancer. Here, the authors report the discovery of naturally occurring ESR1 Y537Cand ESR1 Y537S mutations in two breast cancer cell lines after acquisition of resistance to long-term-estrogen-deprivation.
- Lesley-Ann Martin
- , Ricardo Ribas
- & Mitch Dowsett
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Article
| Open AccessMRAP2 regulates ghrelin receptor signaling and hunger sensing
Melanocortin receptor accessory protein 2 (MRAP2) is an adaptor protein that contributes to melanocortin-4 receptor and prokineticin receptor 1 signalling. Here the authors show that MRAP2 also regulates ghrelin receptor signalling in the hypothalamus and starvation sensing in mice.
- Dollada Srisai
- , Terry C. Yin
- & Julien A. Sebag
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Article
| Open AccessInternalized TSH receptors en route to the TGN induce local Gs-protein signaling and gene transcription
Recent investigations suggest that G-protein-coupled receptors (GPCRs) can signal during intracellular trafficking. Here the authors use fluorescence microscopy approaches to directly visualize and investigate functional consequences of GPCR-mediated signaling at the Golgi/trans-Golgi network.
- Amod Godbole
- , Sandra Lyga
- & Davide Calebiro
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Article
| Open AccessAgonist-induced dimer dissociation as a macromolecular step in G protein-coupled receptor signaling
Frizzled 6 (FZD6) is a G protein-coupled receptor (GPCR) involved in several cellular processes. Here, the authors use live cell imaging and spectroscopy to show that FZD6 forms dimers, whose association is regulated by WNT proteins and that dimer dissociation is crucial for FZD6 signaling.
- Julian Petersen
- , Shane C. Wright
- & Gunnar Schulte
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Article
| Open AccessMolecular mechanism of Gαi activation by non-GPCR proteins with a Gα-Binding and Activating motif
Nonreceptor guanine-nucleotide exchange factors (GEFs) are emerging as important regulators of heterotrimeric G proteins. Here, the authors present structural and mechanistic insights into how a class of nonreceptor GEFs containing the Ga-Binding and Activating motif interact and modulate G proteins.
- Alain Ibáñez de Opakua
- , Kshitij Parag-Sharma
- & Mikel Garcia-Marcos
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Article
| Open AccessDomain-dependent effects of insulin and IGF-1 receptors on signalling and gene expression
Despite being structurally similar, the insulin receptor (IR) and insulin growth factor I receptor (IGF1R) elicit distinct signalling pathways. Here the authors use receptor chimeras to unveil that IR and IGF1R signalling is related primarily to differences in their intracellular juxtamembrane region.
- Weikang Cai
- , Masaji Sakaguchi
- & C. Ronald Kahn
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Article
| Open AccessArrestin-biased AT1R agonism induces acute catecholamine secretion through TRPC3 coupling
Angiotensin II type 1 receptor (AT1R)-mediated acute catecholamine release is modulated by β-arrestin. Here the authors show that β-arrestin-1 recruits the Ca2+channel TRPC3 and the PLCγ to the AT1R-β-arrestin complex, triggering G protein-independent calcium influx and catecholamine secretion.
- Chun-Hua Liu
- , Zheng Gong
- & Jin-Peng Sun
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Article
| Open AccessStructure of the homodimeric androgen receptor ligand-binding domain
The androgen receptor is crucial for the development and physiology of reproductive organs. Here the authors present the structure of the androgen receptor ligand-binding domain bound to dihydrotestosterone, identifying a homodimerization interface that is crucial for receptor activityin vivo.
- Marta Nadal
- , Stefan Prekovic
- & Eva Estébanez-Perpiñá
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Article
| Open AccessSIKs control osteocyte responses to parathyroid hormone
Parathyroid hormone (PTH) is an endogenous hormone and osteoporosis therapeutic that suppresses sclerostin activity. Here the authors develop SIK inhibitors as potential therapeutic tools and use them to show that PTH-cAMP signalling in osteocytes inhibits SIK2 from driving Hdac4/5 nuclear shuttling to suppress sclerostin.
- Marc N. Wein
- , Yanke Liang
- & Henry M. Kronenberg
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Article
| Open AccessDifferential genomic imprinting regulates paracrine and autocrine roles of IGF2 in mouse adult neurogenesis
Selective biallelic expression of certain genes through genomic imprinting are known to play a role in controlling neurogenesis in the adult mammalian brain. Here the authors investigate the role of imprinting in the dosage control of Igf2 and its relevance for the function of IGF2 as a neurogenic regulator in the mouse brain.
- S. R. Ferrón
- , E. J. Radford
- & A. C. Ferguson-Smith
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Internalization and vacuolar targeting of the brassinosteroid hormone receptor BRI1 are regulated by ubiquitination
Ubiquitination of cargo proteins regulates endocytosis in yeast and mammalian cells, however the extent to which this applies to plants is less clear. Martins et al. show that both internalization and vacuolar targetting of the Arabidopsisbrassinosteroid receptor BRI1 are regulated by ubiquitination.
- Sara Martins
- , Esther M. N. Dohmann
- & Grégory Vert
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The nuclear hormone receptor PPARγ counteracts vascular calcification by inhibiting Wnt5a signalling in vascular smooth muscle cells
Vascular calcification is commonly associated with advanced stages of atherosclerosis. Woldtet al. show that the nuclear hormone receptor PPARγ in vascular smooth muscle cells protects mice from vascular calcification by inhibiting Wnt5a signalling triggered by activation of the cell-surface receptor LRP1.
- Estelle Woldt
- , Jérome Terrand
- & Philippe Boucher
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Evidence for activity-regulated hormone-binding cooperativity across glycoprotein hormone receptor homomers
Glycoprotein hormone receptors show negative cooperativity following a single molecule of agonist binding to each receptor dimer. Here, constitutively active receptors are shown to display less cooperative allosteric regulation, suggesting a direct relationship between conformational changes in the transmembrane domain and allosteric behaviour of the receptor dimers.
- Maxime Zoenen
- , Eneko Urizar
- & Sabine Costagliola