Meanwhile, cGAS deletion upregulated profibrotic Yes-associated protein (YAP) signaling in endothelial

into a galaxy of incredible advancements, now powered up with a series of cosmic GPCR events for the year Senior Scientist/Staff Scientist, Computational Chemistry GPCR Activation and Signaling GPCR signalling: Yet

Before the advent of AlphaFold, homology modeling was the most common method for predicting G protein-coupled receptor (GPCR) structures, especially when experimental data were limited. Homology modeling relies on using the known structure of a homologous protein as a template to model the target protein ( Carlsson, J. et al., 2011 ). However, this method has limitations: its accuracy is heavily dependent on the availability and quality of the template structure. For proteins with low sequence similarity to available templates, homology models tend to be less accurate, a notable challenge for GPCRs. GPCRs are dynamic, switching between multiple conformations, and many have only distant homologs with resolved structures, making accurate predictions difficult. The introduction of AlphaFold2 marked a major advancement in the field of GPCR structure prediction. AlphaFold2 uses an AI-driven approach that eliminates the need for structural templates, allowing it to predict structures for GPCRs that were previously difficult to model due to their low sequence homology to known structures. In a recent study on TAAR1, a GPCR linked to central nervous system disorders, researchers compared the performance of AlphaFold and homology models in virtual screening efforts (Diaz-Holguin, A. et al., 2024). The results were striking: AlphaFold2 outperformed homology models, achieving a 60% hit rate for compounds targeting TAAR1, more than double that of the homology models. The AlphaFold-predicted models revealed distinct ligand-binding site shapes, enabling the prioritization of different chemotypes during docking. One of the identified TAAR1 agonists demonstrated promising antipsychotic-like effects in rodent models, reinforcing the value of AlphaFold in drug discovery, especially when experimental structures are unavailable. While AlphaFold2’s ability to predict static structures was groundbreaking, however, GPCRs are highly dynamic proteins and continuously adopt different conformations based on their interactions with ligands and the cellular environment which are crucial for understanding how drugs can selectively target different receptor conformations to achieve therapeutic effects. AlphaFold3, the latest version, has improved on this by modeling interactions with various compounds, including natural ligands, ions, DNA, and RNA. However, AlphaFold3 faces challenges with synthetic ligands, which are central to pharmaceutical development. It excels in modeling interactions with natural ligands but struggles to generalize this accuracy to synthetic compounds, limiting its utility in drug discovery involving novel drug-like molecules. While AlphaFold provides an excellent foundation for generating hypotheses in drug discovery, it is not a standalone solution. To fully understand GPCR behavior and optimize drug targeting across multiple receptor states, experimental validation such as X-ray crystallography, cryo-EM or NMR are still essential for confirming predictions, refining models, and exploring the functional states of GPCRs. Additional kinetic validations must also be verified to comprehend the functions of the proteins. Future iterations of AlphaFold, or its integration with other computational techniques, could help overcome these limitations, leading to more comprehensive models that bridge the gap between computational predictions and real-world data. References: Carlsson, J.  et al.  Ligand discovery from a dopamine D3 receptor homology model and crystal structure. Nat Chem Biol   7 , 769-778 (2011).   https://doi.org/10.1038/nchembio.662 Diaz-Holguin, A.  et al.  AlphaFold accelerated discovery of psychotropic agonists targeting the trace amine-associated receptor 1. Sci Adv   10 , eadn1524 (2024).   https://doi.org/10.1126/sciadv.adn1524

allosteric modulation-based drug discovery and development, announced today that it will issue its full-year

company pioneering allosteric modulation-based drug discovery and development, today reported its half-year

July 2022 "G.CLIPS biotech is 2 years old today🎂.

July 2022 "Today we are celebrating ten years of Exscientia! of a global company with locations in the UK, U.S., Austria, and Japan which IPO’d in October last year We’re excited about delivering the next ten years of Exscientia and advancing AI to design better drugs

Coming on its 15th year, Third Rock Ventures announced its sixth fund today — and largest one by far

October 2022 "Systolic heart failure (HF) is a chronic clinical syndrome characterized by the reduction in cardiac function and still remains the disease with the highest mortality worldwide. Despite considerable advances in pharmacological treatment, HF represents a severe clinical and social burden. Chronic human HF is characterized by several important neurohormonal perturbations, emanating from both the autonomic nervous system and the adrenal glands. Circulating catecholamines (norepinephrine and epinephrine) and aldosterone elevations are among the salient alterations that confer significant hormonal burden on the already compromised function of the failing heart. This is why sympatholytic treatments (such as β-blockers) and renin-angiotensin system inhibitors or mineralocorticoid receptor antagonists, which block the effects of angiotensin II (AngII) and aldosterone on the failing heart, are part of the mainstay HF pharmacotherapy presently. The adrenal gland plays an important role in the modulation of cardiac neurohormonal stress because it is the source of almost all aldosterone, of all epinephrine, and of a significant amount of norepinephrine reaching the failing myocardium from the blood circulation. Synthesis and release of these hormones in the adrenals is tightly regulated by adrenal G protein-coupled receptors (GPCRs), such as adrenergic receptors and AngII receptors. In this review, we discuss important aspects of adrenal GPCR signaling and regulation, as they pertain to modulation of cardiac function in the context of chronic HF, by focusing on the 2 best studied adrenal GPCR types in that context, adrenergic receptors and AngII receptors (AT 1 Rs). Particular emphasis is given to findings from the past decade and a half that highlight the emerging roles of the GPCR-kinases and the β-arrestins in the adrenals, 2 protein families that regulate the signaling and functioning of GPCRs in all tissues, including the myocardium and the adrenal gland." Read more at the source #DrGPCR #GPCR #IndustryNews

Beth:  “I was invited to join Crinetics a few years ago by some former colleagues and their description Beth:  “Yes.  There are a lot of learning opportunities at Crinetics. 

phosphorylation at Tyr357, as shown by using the SFK inhibitors dasatinib, saracatinib, the preferential YES1 inhibitor CH6953755, short interfering RNA (siRNA)-mediated knockdown of YES1 and transfection of epitogue-tagged , our results also demonstrate that exposure to SFK inhibitors, including dasatinib or knockdown of YES

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What challenges will researchers overcome in the next 10 years? AB: One of the big challenges that the field will have to face in the next 10 years is deciphering the I said yes as soon as they approached me. together some of the hottest adhesion GPCR research going on right now and set the tone for the upcoming years

Every year, with the month of October, comes the excitement of the Nobel session to the global scientific Ye, R. D. Regulation of nuclear factor κB activation by G-protein-coupled receptors.

Rodríguez-Pérez , Gemma Navarro , José Labandeira-García , Rafael Franco Endomembrane GPCR signaling: 15 years of human odorant receptor multigene family Reviews, GPCRs, and more Endomembrane GPCR signaling: 15 years

The choice of model systems, such as yeast, bacteria, or mammalian cells, can heavily influence the method's

Receive $3-Million Award from ARPA-H’s Sprint for Women’s Health Nxera Pharma Wins Biotech Company of the Year and Financing Deal of the Year at the Citeline Japan Awards 2024 GPCR therapies: Eight promising biotechs

High-throughput G protein-coupled receptor-based autocrine screening for secondary metabolite production in yeast

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activity-modifying proteins Nicholas Kapolka , Geoffrey Taghon , and Daniel Isom  for their research on Advances in yeast Signaling: A Study of the Interplay Between Structure, Energy, and Function Engineering a GPCR-based yeast GPCRs, and more G protein-coupled receptor (GPCR) gene variants and human genetic disease Advances in yeast

High-throughput G protein-coupled receptor-based autocrine screening for secondary metabolite production in yeast

., CEO and Founder of Crinetics Pharmaceuticals, as an Entrepreneur Of The Year® 2024 Pacific Southwest

G protein-coupled receptors (GPCRs) are major drug targets, yet their complex and dynamic structures

replication Methods & Updates in GPCR Research Evaluation and comparison of colorimetric outputs for yeast-based

dynamics ( e.g FLAsH biosensor [11]), cAMP production (e.g CAMYEL assay [12]) , and ERK activity (e.g YEN