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Welcome back GPCR fans, The pace of GPCR innovation is accelerating at a rate that can be difficult to Learn how his research aims to develop models that can distinguish between active and inactive ligands gap between disciplines:  Get practical advice from a computational expert on how wet-lab scientists can The right information at the right time can mean the difference between a breakthrough and a dead end GPCR Premium Membership gives you direct access to the experts and insights that can redefine your work

Multiple 14-3-3 isoforms exist, and a GPCR can differentially interact with different 14-3-3 isoforms We found that some agonist-induced GPCR/14-3-3 signal intensities can rapidly decrease. Furthermore, we found that certain GPCR ligands can regulate GPCR/14-3-3 signals temporally, suggesting

,  Yongfeng Liu ,  Marion Lanier ,   Brian K Shoichet ,  Esther Martinborough ,  Jonathan F Fay ,  Can Cao ,   Bryan L Roth , et al. GPCR Events You can begin organizing and marking a few dates in 2025 .

their investigation on Molecular insights into G protein coupling specificity at a class A GPCR Jianjun Cao If you have any research you would like to showcase to our community, you can submit a poster presentation

facilitates cryo-EM structure determination of a Family A GPCR Jun Xu , Geng Chen , Haoqing Wang , Sheng Cao Starting in 2025, only Premium Members can access Classified GPCR News.

The Importance of Binding in Drug Action In pharmacology, binding must happen before any drug effect can When a drug binds to its target, it initiates a series of events that can lead to a physiological response This knowledge can guide modifications to improve binding affinity and bioavailability. This understanding can enhance your appreciation for drug development and therapeutic action. By embracing these concepts, we can pave the way for more effective treatments in the future.

But it’s also the reason a promising lead can turn toxic overnight. This session unpacks how persistent binding can either accelerate your program—or quietly kill it. Such interactions can disrupt metabolic detoxification and lead to delayed, systemic toxicity. Getting this wrong doesn’t just slow a program—it can mislead the entire development strategy . Irreversible binding can turn enzyme interactions into make-or-break kinetic events.

They can also further pharmacological and structural studies, as they can be used to determine receptor It can be appreciated how fast the ligand diffuses and is distributed homogeneously within monolayers This can lower the quality of long-term imaging studies but can be fixed by using stable fluorescent This can be fixed by using fluorescent dyes that emit at longer wavelengths, where fluorescence from Confocal microscopy is a technique that can be used to mitigate this issue.

For GPCR drug discovery, those hidden details can determine whether a compound advances or stalls. By modulating receptor expression or sensitivity, we can shift the “lens” through which drug activity These aren’t abstract academic puzzles—they’re decision points that can make or break a program. Monthly AMAs  where you can challenge Terry with your toughest questions. Decades of insight distilled  into frameworks you can apply immediately.

These systems are used here as resolved examples of how interface binding can stabilize specific signaling Key implications: SBI-553 illustrates how arrestin signaling can be stabilized through direct receptor–Gαo PCO371 shows that G protein bias can be achieved through intracellular binding that suppresses arrestin This limitation affects how signaling data can be interpreted when receptor behavior depends on cell Allosteric modulators can alter signaling efficacy without changing ligand affinity, uncoupling binding

assays—particularly membrane-based radioligand binding—often provide high-throughput measurements, yet they can , where nuanced shifts in receptor conformation affect signaling outcomes, a whole-cell environment can This dataset highlights how HCS can be used both to triage compound series and to extract quantitative and in concentration–response formats  Why image-based confirmation (and transparent Ki reporting) can Using HEK-293 cells stably expressing CB2R, fluorescent tracers such as CELT-331 can report on ligand

difference between orthosteric vs. allosteric mechanisms isn’t just academic — an orthosteric antagonist can That can be powerful but blunt. This means they can be more selective, avoid pathway saturation, and preserve physiological nuance. Unlike orthosterics, they can discriminate between agonists, pathways, and even durations of action. Translational Relevance: From Bench to Clinic Misjudging orthosteric vs allosteric behavior can derail

They are ligands labeled with radioactive isotopes which can be used in binding assays to quantify other Besides binding assays, they can also be used to study receptor density, binding sites and ligand kinetics This can be done with agonists, antagonists, reverse agonists in the case of GPCRs. Figure 1. Fluorescent ligands can be used at a broader range of concentration without losing accuracy, as well Live-cell imaging:  Fluorescent ligands can be used to study cellular and tissue location of a receptor

His group is trained to explain exactly what a model can predict and where its limits are. If docking can suggest binding modes but can’t resolve nanomolar potency differences, they say so. No single discipline can cover all the ground . Modelers can generate binding hypotheses, but they remain untested until validated experimentally. He resists hype, focusing instead on predictions collaborators can actually use.

What initially appears mechanistically clear can become more nuanced when additional experiments are Functional assays can suggest clarity while quietly masking complexity, creating the illusion of competitive It can redirect chemistry strategy, distort translational assumptions, and conceal liabilities that emerge — A Distinctive Allosteric Readout Allosteric systems exhibit probe dependence: the same modulator can High-expression systems maximize detection sensitivity and can reveal subtle efficacies.

Industry can build skills that academia often overlooks. Passion can lead to groundbreaking discoveries and a fulfilling career. However, embracing uncertainty can lead to unexpected opportunities. In life and career, taking risks can lead to personal and professional growth. This mindset can lead to a more fulfilling and successful career.

You can check what we do here on our website!   This conjugation is very useful for tagging biomolecules and can also be used to develop fluorescent Thanks to the unique linker structure we obtain, which can be divided into three differentiated parts , we can modify the rigidity of the linker as well as the physicochemical properties of the whole probe This property comes from the wide chemical space this reaction can access – we can substitute one reagent

Two compounds can show identical affinities on paper, but their biological outcomes can differ dramatically Every day spent misunderstanding what your assays are truly showing you can lead to costly missteps—wasted is essential for pipeline efficiency: How fast a ligand binds (k₁) and how long it stays bound (k₂)  can conditions —such as the presence of endogenous ligands— change kinetic behavior , and ignoring this can equilibrium Interpret competition experiments with confidence Recognize how kinetic rate constants can

Even the most elegant GPCR ligand can fail if it never reaches its receptor. They can metabolize, inactivate, or transform your compound, sometimes into a toxic byproduct, other By mastering the difference, discovery teams can anticipate resistance, tune selectivity, and design Kenakin dissects how P450s can be both protective and problematic. Monthly AMAs  where you can challenge Dr. Kenakin with your own enzyme or GPCR interaction puzzles.

It is about building a team that can operate when clarity is missing. They determine whether skills can be applied at all.   Skills determine what someone can do when conditions are stable. They start asking whether that person can still be effective when the ground shifts under their feet. The goal is to build a team that can operate while uncertainty is present. 👉 Skills matter.

By measuring the way these cells scatter light and emit fluorescence, they can be identified, quantified These limitations can impact data quality, reproducibility, and assay flexibility. Ideal for live cell low cytometry, which means you can monitor while preserving cellular integrity. 3 Innovations in the fluorophore tags, such as pH sensitive probes, can further improve signal-to-noise Autofluorescence and multiplexing: Using far-red or near-infrared fluorophores can reduce background

One wrong assumption about how your molecule behaves in a living system can sink months of work and millions Reflex arcs, compensatory pathways, and receptor trafficking can turn your expected outcome on its head In this session, you’ll gain: ✅ A mental model you can trust  for predicting how GPCR ligands behave You’ll understand why this is good news, not bad data, and how it can actually prevent harmful reflex Some can make a mediocre drug shine.

Can we leverage structural and computational insights not just to explain receptor–ligand interactions computational chemistry, and drug discovery —rethinking how simulations, docking, and machine learning can Common questions in the group include: Can we forecast ligand efficacy or selectivity? Can we design compounds that trigger biased signaling? But part of their rigor lies in restraint. For drug discovery executives, the message is clear: predictive modeling can shorten timelines, reduce

DMS can be used to comprehensively assess the functional impact of mutations in a candidate protein, helping to validate whether drugs can effectively target it. This high-resolution mapping can confirm the protein’s role in disease pathology and highlight allosteric By examining how mutations in the target protein affect its interaction with the drug, researchers can Mutations in target proteins can lead to decreased drug affinity and/or potency, rendering treatments

What makes you excel in the lab can quietly sabotage your leadership in the boardroom. 👉 Scientific those same instincts to analyze deeply, minimize error, and delay action until “enough” data is in can   ✅  This post explores how scientific thinking can become a leadership liability and what mindset In research, acting on incomplete or shaky data can destroy your credibility. But in the startup environment, these instincts can quickly become liabilities.

(think batteries and balance scales), Terry reveals why different tissues—and even different assays—can From oxymetazoline to oxotremorine, discover how drugs can show up as full agonists in one system and

walks you through: What dose-response curves are and why they’re indispensable How curve-fitting models can Ready to grasp how a curve can mislead—or enlighten?

signaling  (also called functional selectivity), means that two molecules targeting the same receptor can Achieving that objective demands assays that can actually see the difference.  A single GPCR can stabilize multiple active conformations, each of which preferentially couples to a , PAMs and NAMs), and crucially, can do so in a pathway-selective manner. Allosteric modulators, which do not compete directly at the orthosteric site, can be missed entirely

Every day spent misunderstanding the meaning of apparent affinity differences can slow your project’s But as Terry Kenakin reveals, this interpretation can be misleading, and sticking with it could slow doesn’t necessarily reflect what’s happening in a physiological context, and misunderstanding this can Misunderstandings at this level can delay optimization cycles, result in wasted SAR iterations, or cause

Work on receptors such as GLP-1R and MC4R has demonstrated that internalized GPCRs can continue to signal agonist-induced conformational change to leave the cell surface — it requires an active state, and antagonists can At the MC4 receptor, alpha-MSH–driven responses can be washed off and antagonized by AgRP — these are BRET-based assays can quantify beta-arrestin recruitment and, depending on the assay design, distinguish Experimentally, this steady state between recycling and degradation can be dissected by blocking one