16 papers · ranked by Valyu relevance
D. C. Indurthi, A. Auerbach
Agonists are evaluated by a concentration-response curve (CRC), with a midpoint (EC_50_) that indicates potency, a high-concentration asymptote that indicates efficacy and a low-concentration asymptote that indicates constitutive activity. A third agonist attribute, efficiency (η), is the fraction of binding energy…
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…
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…
Ashley N. Nilson, Daniel E. Felsing, Pingyuan Wang, Manish K. Jain + 2 more
The dopamine D1 receptor (D1R) has fundamental roles in voluntary movement and memory and is a validated drug target for neurodegenerative and neuropsychiatric disorders. However, previously developed D1R selective agonists possess a catechol moiety which displays poor pharmacokinetic properties. The first selective…
Brian MacTavish, Di Zhu, Jinsai Shang, Qianzhen Shao + 3 more
Nuclear receptors (NRs) are thought to dynamically alternate between transcriptionally active and repressive conformations, which are stabilized upon ligand binding. Most NR ligand series exhibit limited bias, primarily consisting of transcriptionally active agonists or neutral antagonists, but not repressive inverse…
Taylor L. Mighell, Ben Lehner
G-protein coupled receptors (GPCRs) are the most abundant class of human receptors and drug targets. The vast majority of GPCR drugs bind the conserved orthosteric pocket, which can lead to non-specificity and toxicity. Precision modalities such as biased signaling and allosteric modulation could lead to GPCR…
Edward L. Stahl, Laura M. Bohn
In a recent report by 16 (1), it was suggested that low intrinsic agonism, and not biased agonism, leads to an improvement in the separation of potency in opioid-induced respiratory suppression versus antinociception. Although the compounds that were tested have been shown to display G protein signaling bias in prior…
Taylor L. Mighell, Ben Lehner
G protein-coupled receptors (GPCRs) are the largest family of human receptors and drug targets, but how the signaling properties of receptors are encoded in their sequence is incompletely understood. Most GPCR drugs bind a conserved orthosteric pocket, which can result in non-specificity, toxicity and clinical failure.…
Yue Chen, Nour Aldin Kahlous, Marcus Saarinen, Sergio Perez Conesa + 3 more
G protein-coupled receptors (GPCRs) control numerous physiological processes and are important therapeutic targets. Despite major research efforts, rational design of drugs that stimulate GPCR signaling is challenging because the molecular basis of activation remains poorly understood. Here, a combination of molecular…
Shayan Amiri, Mohamad-Reza Aghanoori, Darrell R. Smith, T. M. Zaved Waise + 5 more
Previous studies indicate that both pirenzepine (PZ), a selective orthosteric muscarinic acetylcholine type 1 receptor (M_1_R) antagonist, and muscarinic toxin 7 (MT7), a negative M_1_R allosteric modulator (NAM), act via M_1_R to promote neuritogenesis in cultured adult rodent primary dorsal root ganglia (DRG) sensory…
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…
Yang Lee, Tony Warne, Rony Nehmé, Shubhi Pandey + 6 more
The β_1_-adrenoceptor (β_1_AR) is a G protein-coupled receptor (GPCR) activated by the hormone noradrenaline, resulting in the coupling of the heterotrimeric G protein G_s_^1^. G protein-mediated signalling is terminated by phosphorylation of the receptor C-terminus and coupling of β-arrestin 1 (βarr1, also known as…
Fabian Bumbak, Miquel Pons, Asuka Inoue, Juan Carlos Paniagua + 7 more
Unlike many signaling proteins that function as binary switches between ‘on and off’ states, G protein-coupled receptors (GPCRs) exhibit basal activity that can be increased or decreased by numerous ligands. A given receptor can recognize multiple ligands, allosteric modulators, and transducers to create a complex free…
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…
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.…