October 2022 Structural perspectives on the mechanism of signal activation, ligand selectivity and allosteric opportunities to examine the dynamic fluxes in the 3D architecture of the receptors, as the basis of ligand selectivity Constituent structural motifs cooperatively transform ligand selectivity into specific functions, thus

August 2022 GPCRs steer G i and G s selectivity via TM5-TM6 switches as revealed by structures of serotonin important neurotransmitter that activates 12 different G protein-coupled receptors (GPCRs) through selective The structural basis for G protein subtype selectivity by these GPCRs remains elusive. that transmembrane helices TM5 and TM6 alternate lengths as a macro-switch to determine receptor's selectivity Together, these results present a common mechanism of Gs versus Gi protein coupling selectivity or promiscuity

therapeutic drugs have been developed to treat these diseases; however, they lack receptor subtype selectivity a 2.2 Å resolution room temperature crystal structure of the human S1P5 receptor in complex with a selective unique ligand-binding mode, involving an allosteric sub-pocket, which clarifies the receptor subtype selectivity

October 2022 Discovery and In Vivo Evaluation of ACT-660602: A Potent and Selective Antagonist of the hit, we describe the iterative optimization of a chemical series culminating in the discovery of the selective

recently presented this important pre-clinical work at SIRS2022 confirming the ability of the highly selective

November 2022 "Some G protein-coupled receptor (GPCR) ligands act as "biased agonists" that preferentially activate specific signaling transducers over others. Although GPCRs are primarily found at the plasma membrane, GPCRs can traffic to and signal from many subcellular compartments. Here, we determine that differential subcellular signaling contributes to the biased signaling generated by three endogenous ligands of the GPCR CXC chemokine receptor 3 (CXCR3). The signaling profile of CXCR3 changes as it traffics from the plasma membrane to endosomes in a ligand-specific manner. Endosomal signaling is critical for biased activation of G proteins, β-arrestins, and extracellular-signal-regulated kinase (ERK). In CD8 + T cells, the chemokines promote unique transcriptional responses predicted to regulate inflammatory pathways. In a mouse model of contact hypersensitivity, β-arrestin-biased CXCR3-mediated inflammation is dependent on receptor internalization. Our work demonstrates that differential subcellular signaling is critical to the overall biased response observed at CXCR3, which has important implications for drugs targeting chemokine receptors and other GPCRs." Read more at the source #DrGPCR #GPCR #IndustryNews Subscribe to the Dr. GPCR Newsletter HERE

September 2022 Fly casting with ligand sliding and orientational selection supporting complex formation with an accompanying rapid reduction of the molecular orientational variety of bosentan (orientational selection

April 2022 Addex Expands Pipeline With Selective M4 Positive Allosteric Modulator Program For The Treatment Of Schizophrenia & Other Psychotic Disorders " New Series of Potent and Selective Compounds Identified pioneering allosteric modulation-based drug discovery and development, announced today that it has moved a selective

August 2022 GRK2 selectively attenuates the neutrophil NADPH-oxidase response triggered by β-arrestin

Taken together, our study lays the groundwork for understanding aGPCR activation and G-protein-coupling selectivity

pharmacology, biology, behavior, and neurophysiology "The awareness of the potential importance of functional selectivity A major pan-receptor focus has been to identify GPCR-selective ligands that have bias in G protein-dependent

May 2022 "We are thrilled to announce that our co-founder Margaux Duchamp has been selected as a 30

subset of this field with accelerating importance: transducer biosensors measuring receptor-coupling and selectivity

This distinction is essential for designing drugs that selectively target these residues to achieve desired evolutionary standpoint, the study reveals that residues critical for β2AR function are under intense selective pressure, while others are more mutation-tolerant.

School of Medicine faculty members — Susanna Naggie, MD , and Sudarshan Rajagopal, MD, PhD — have been elected Naggie and Rajagopal are two of 95 new members elected to the society for 2022.

and the binding of a ligand, as well as interactions with signaling molecules like G proteins, can selectively While this has the potential to enhance GPCR subtype-selectivity, it also presents a significant challenge Moreover, they have the potential to enhance target selectivity, which can arise from greater sequence GPCRs functional selectivity Recent research has revealed a more intricate understanding of GPCR behavior This phenomenon is termed "stimulus-trafficking," "biased agonism," or "functional selectivity" (Urban

What is the molecular basis that determines that GPCRs bind selectively or promiscuously to different analysis of these complexes revealed two important aspects: the specific residues involved in ligand selectivity GPCRs field as it supports the development of alternatives to improve drug design to optimize receptor selectivity relative lengths of TM5 and TM6 in serotonin receptors function as a macro-switch to determine the selectivity The differences found at the residue level are referred to as micro-switches that will define a selective

N-terminal alterations turn the gut hormone GLP-2 into an antagonist with gradual loss of GLP-2 receptor selectivity purpose: To fully elucidate the regulatory role of the GLP-2 system in the gut and the bones, potent and selective To examine selectivity, COS-7 cells expressing human GLP-1 or GIP receptors were assessed for cAMP accumulation

the above lightly represent the potential applications of Nbs to facilitate the development of more selective Binding to cryptic epitopes and conformational selection: Nanobodies have a unique shape that allows Generation, selection and functional expression: Nanobodies can be obtained by immunizing a camelid and Combinatorial biology methods such as phage display, yeast display, and ribosome display can be used to select Nb35: This nanobody selectively binds to the β2AR·Gs complex and prevents the dissociation of the nucleotide-free

We also synthesized a series of small molecule ligands which acted as selective agonists for ACKR3 as Using select point mutations, we studied the molecular characteristics that determine the ability of The development of more selective ACKR3 ligands should allow us to better appreciate the unique roles In this study, novel selective ligands for ACKR3 were discovered and the site of interactions between

While this has the potential to enhance GPCR subtype-selectivity, it also presents a significant challenge Moreover, they have the potential to enhance target selectivity, which can arise from greater sequence allosteric sites among receptor subtypes when compared to the conserved orthosteric region, or from selective On the other hand, selectivity could be achieved by merging both orthosteric and allosteric pharmacophores Biased allosteric modulators can enhance the safety and efficacy of GPCR-targeted therapeutics by selectively

Functional activity of selected compounds was assessed across 5-HT2A, 5-HT2B, and 5-HT2C receptors, with several compounds demonstrating subtype selectivity and high potency, some with sub-nanomolar EC50 values , indicating strong and selective receptor binding.

June 2022 "CRN04894 Selected for Oral Presentation SAN DIEGO, June 8, 2022 — Crinetics Pharmaceuticals adrenal hyperplasia (CAH) and other conditions driven by excess adrenocorticotropic hormone (ACTH), were selected

We identified gambogic acid (GA), a natural prenylated xanthone, selectively targeting GPR108. as a promising therapeutic target of cancer, and provided a small molecule inhibitor GA directly and selectively

OR4N4 is the most highly expressed OR in human spermatozoa and is an example of a highly and selectively However, selection of promising candidates is not an easy task. Due to the diversity of the OR family it will be critical to select potential targets to modulate in In order to target ectopic ORs there is a need to identify selective agonists or antagonists, where the Selective screening assays for ectopic ORs as well as investment on the structural characterization of

question, we studied mice that express a Gs-coupled designer G protein-coupled receptor (Gs-DREADD or GsD) selectively CRF2 receptor) and studied the acute metabolic effects of activating these receptors in vivo by highly selective GsD signaling in SKM impaired glucose tolerance in lean and obese mice by decreasing glucose uptake selectively Conclusions: Selective activation of Gs signaling in SKM causes an acute increase in blood glucose levels

Jianming Han , Tao Che  for their analysis of GPCR-G protein selectivity revealed by structural pharmacology Principles of Pharmacology in Drug Discovery II - Advanced Methods for the Optimization of Candidate Selection Targeting G protein-coupled receptors for heart failure treatment RAMP and MRAP accessory proteins have selective Molecular Insights into GPCR Function Cryo-EM advances in GPCR structure determination GPCR-G protein selectivity

Deletion of phospholipase Cβ3 (PLCβ3), or selective inhibition of Gβγ regulation of PLCβ3, enhances the upstream regulators, Gβγ or Gq, ex vivo in periaqueductal gray (PAG) slices increased the potency of the selective