23 papers · ranked by Valyu relevance
Rustin R. Lovewell, Solomon Langermann, Dallas B. Flies
The immune system maintains the health of an organism through complex sensing and communication mechanisms. Receptors on the surface of immune cells respond to stimuli resulting in activity described at its most basic as inhibitory or stimulatory. Significant progress in therapeutic intervention has occurred by…
Bradley T Andresen
Biased agonism is one of the fastest growing topics in G protein-coupled receptor pharmacology; moreover, biased agonists are used in the clinic today: carvedilol (Coreg®) is a biased agonist of beta-adrenergic receptors. However, there is a general lack of understanding of biased agonism when compared to traditional…
Wolfgang Sadee, Mariana Spetea
G-protein-coupled receptors (GPCRs) are ubiquitous sensors and regulators of cellular functions. Each GPCR exists in complex aggregates with multiple resting and active conformations. Designed to detect weak stimuli, GPCRs can also activate spontaneously, resulting in basal ligand-free signaling. Agonists trigger a…
Michael J. Robertson, Makaía M. Papasergi-Scott, Maria Claudia Peroto, Balazs R. Varga + 2 more
Distinct ligands for the same G-protein coupled receptor (GPCR) activate intracellular signaling partners to varying extents, but the molecular mechanisms driving these differences remains elusive. Hypothesizing that such differences in signaling efficacy may be captured structurally in intermediate states under…
James P. Higham, David Colquhoun
A fundamental mistake in receptor theory has led to an enduring misunderstanding of how to estimate the affinity and efficacy of an agonist. These properties are inextricably linked and cannot be easily separated in any case where the binding of a ligand induces a conformation change in its receptor. Consequently…
Karla K.V. Haack, Nael A. McCarty
G Protein Coupled Receptors (GPCRs) represent the largest family of membrane proteins in the human genome, are the targets of approximately 25% of all marketed pharmaceuticals, and the focus of intensive research worldwide given that this superfamily of receptors is as varied in function as it is ubiquitously expressed…
Matthieu Colom, Benjamin Vidal, Luc Zimmer
Positron emission tomography (PET) is a molecular imaging modality that enables in vivo exploration of metabolic processes and especially the pharmacology of neuroreceptors. G protein-coupled receptors (GPCRs) play an important role in numerous pathophysiologic disorders of the central nervous system. Thus, they are…
Friederike Wunsch, Michael Kauk, Jenny Filor, Gerhard Wolber + 3 more
For the prototypic M_2_ receptor it has been previously demonstrated that dualsteric partial agonists can stabilize both, active and inactive receptor states, but it remains unclear whether orthosteric partial agonists have a similar mechanism. Here, we apply dynamic pharmacophores to unveil binding mode ensembles for…
Yoonji Lee, Sun Choi, Changbong Hyeon
Dynamics and functions of G-protein coupled receptors (GPCRs) are accurately regulated by the type of ligands that bind to the orthosteric or allosteric binding sites. To glean the structural and dynamical origin of ligand-dependent modulation of GPCR activity, we performed total ∼ 5 µsec molecular dynamics simulations…
Yuya Koga, Kento Kawaharazuka, Moritaka Onitsuka, Tasuku Makabe + 5 more
'Kei Tsuzuki' 'Yusuke Omura' 'Yuki Asano' 'Kei Okada' 'Masayuki Inaba'] Abstract— In recent years, some research on musculoskeletal humanoids is in progress. However, there are some challenges such as unmeasurable transformation of body structure and muscle path, and difficulty in measuring own motion because of lack…
Authors not listed
Targeting retinoic acid-related orphan receptor γ (RORγ) with inverse agonists presents a promising therapeutic strategy for treating autoimmune diseases, including psoriasis, rheumatoid arthritis, and multiple sclerosis. Through structure-based virtual screening, we identified a lupane-type pentacyclic triterpenoid…
Sabine Willems, Romy Busch, Felix Nawa, Marco Ballarotto + 12 more
Nuclear receptor related 1 (Nurr1, NR4A2) is a ligand-sensing transcription factor with neuroprotective and anti-inflammatory roles widely distributed in the CNS. Pharmacological Nurr1 modulation is considered a promising experimental strategy in Parkinson's and Alzheimer's disease but target validation is incomplete.…
Etienne Khoury, Stéphanie Clément, Stéphane A. Laporte
G protein-coupled receptors (GPCRs) are seven-transmembrane proteins that participate in many aspects of the endocrine function and are important targets for drug development. They transduce signals mainly, but not exclusively, via hetero-trimeric G proteins, leading to a diversity of intracellular signaling cascades.…
Laura Riccetti, Romain Yvinec, Danièle Klett, Nathalie Gallay + 5 more
'Yves Combarnous' 'Éric Reiter' 'Manuela Simoni' 'Livio Casarini' 'Mohammed Akli Ayoub'] Human luteinizing hormone (LH) and chorionic gonadotropin (hCG) have been considered biologically equivalent because of their structural similarities and their binding to the same receptor; the LH/CGR. However, accumulating…
Spencer Kim, Dylan Gray, Michelle Shanguhyia, Rachel Steinhardt
Recreating the signaling profile a chemical synapse to analyze serotonin receptor activation is a challenge. This is due in part to the kinetics of the synapse, where neurotransmitters are rapidly released and quickly cleared by active reuptake machinery. One strategy to produce a rapid rise in a bio-orthogonally…
Ranjita Dutta-Roy, Christian Rosenmund, Stuart J. Edelstein, Nicolas Le Novère
'Nicolas Le Novère'] Modulation of the properties of AMPA receptors at the post-synaptic membrane is one of the main suggested mechanisms underlying fast synaptic transmission in the central nervous system of vertebrates. Electrophysiological recordings of single channels stimulated with agonists showed that both…
Authors not listed
GPR3 belongs to the protein superfamily of G protein-coupled receptors (GPCRs) and plays a central role in both benign and malignant physiological processes, such as energy expenditure in adipocytes and Alzheimer’s disease pathology, respectively. Despite the therapeutic potential of both receptor agonists and inverse…
Simon Lind, André Holdfeldt, Jonas Mårtensson, Kenneth L. Granberg + 2 more
Non-activating positive allosteric modulators specific for free fatty acid receptor 2 (FFAR2) increased the activity induced by orthosteric agonists to trigger a rise in intracellular Ca^2+^ ([Ca^2+^]_i_) and activate the O_2_^−^ producing neutrophil NADPH-oxidase. In addition, two allosteric modulators (Cmp58 and…
Zach Walsh, Ozden Merve Mollaahmetoglu, Joseph Rootman, Shannon Golsof + 4 more
'Shannon Golsof' 'Johanna Keeler' 'Beth Marsh' 'David J. Nutt' 'Celia J. A. Morgan'] In the original publication,1 an error was made in the introduction. In the first sentence of the Background section, ‘agonist’ should have been ‘antagonist’. This has now been corrected in both the online PDF and HTML versions of this…
Xiaohan Zhou, Maria Shemeteva, Louis-Phillipe Picard, François Simon + 5 more
Many G protein coupled receptors (GPCRs) exhibit constitutive (basal) activity, where they can signal in the absence of ligand binding through spontaneous conformational transitions that facilitate G protein coupling and downstream signaling. This intrinsic baseline activity is critical for cellular homeostasis and can…
Authors not listed
Allosteric modulators offers a promising approach for targeting receptor function in pathological contexts. Although numerous orthosteric ligands have been developed, the discovery of allosteric inhibitors remains limited, hindered by challenges with identifying modulators and the perceived lower druggability of…
Alice Valentini, Bethany Dibnah, Marija Ciba, Trond Ulven + 2 more
G protein coupled receptors (GPCRs) are the largest family of signalling proteins and highly successful drug targets. To date, most GPCR drugs interact with the binding pocket for the natural ligand, typically near the extracellular part of the transmembrane region. Recent advancements in structural biology have…
Joshua D. Frenster, Hediye Erdjument-Bromage, Wenke Liu, Gabriele Stephan + 13 more
GPR133 (ADGRD1), an adhesion G protein-coupled receptor, supports growth of glioblastoma, a brain malignancy. We demonstrated that GPR133 is intramolecularly cleaved, and that dissociation of its N-terminal and C-terminal fragments (NTF and CTF) at the plasma membrane correlates with increased receptor signaling.…