Even the most elegant GPCR ligand can fail if it never reaches its receptor. The transition from “magic” to mechanistic understanding, championed by pioneers like A.J. 🎥  Coming Soon: Live AMA with Dr. Terry Kenakin This Month’s Live AMA — October 30 at 12 PM EST Join Dr. Kenakin live for an open Q&A session designed for discovery scientists.

This Week’s GPCR Intelligence: If you want cleaner decisions, start with the system—then the ligand. GPCR; a bidirectional GPCR switch modulates immune signaling; a machine-learning tool predicts GPCR–ligand Plus: new research on CaSR, leptin signaling, and inflammation-linked GPCRs — and curated roles in computational Premium delivers the full details, links, and expert commentary every week. Prediction, it turns out, is only powerful if you understand its limits. 🎧 Catch up while you wait:

Eric Trinquet shares what it really takes to bring a product to life—from sketch to shelf. But a pattern emerged: some scaffolds showed dual responsiveness to pH through lifetime and brightness And for those on the front lines of GPCR science, it’s a new lens to see what’s always been there—just 🎧 Listen to the full podcast episode here ⸻ More about Revvity pHSense Reagents GPCR Reagents Revvity GPCR X Revvity Collaboration ⸻ Want more like this? 👉 Join the Dr.

It’s about revealing therapeutic liabilities before  they derail development. Think of it this way: most receptors behave like switches—they stay off until flipped. But some leak current, like a switch glowing faintly in the dark. A growing on-demand library  of expert pharmacology lessons to revisit anytime. Pipeline efficiency isn’t luck—it’s literacy.

This week’s edition links ligand mechanism to the decisions that shape affinity, efficacy, selectivity Each week we highlight the decisions that move GPCR projects forward—from pharmacology essentials to ligand  Studies on active-state GPCR ensembles and their transducer coupling, biased angiotensin receptor ligands For GPCRs, fluorescent ligands have quietly become one of the most versatile technologies—supporting The Advantages Live-cell imaging:  visualize receptor–ligand interactions in real time, without disturbing

Depending on the type of GPCR, it can lead to different secondary messengers , like cAMP, IP3, which GPCR signaling: (A) an orthosteric ligand (orange) binds an inactive GPCR, the β2 adrenergic receptor Their physiological ligands are not fully understood, which opens new treatment possibilities. Some of the advantages of using fluorescent ligands for this are: Live-cell imaging:  receptor-ligand A Robust and Efficient FRET-Based Assay for Cannabinoid Receptor Ligands Discovery.

Developed to address long-standing challenges in GPCR internalization assays , pHSense™ reagents  combine live-cell developed to overcome three persistent barriers in internalization studies : Complex imaging workflows Limited addition to Revvity’s GPCR reagent portfolio , which supports every stage of the signaling cascade: GPCR ligand binding  – TR-FRET, radioligand, Tag-lite® G-protein activation  – cAMP, IP-One, GTP assays β-arrestin to the Podcast with Revvity’s Eric Trinquet → Explore the pHSense™ Reagent Line → Browse Revvity’s GPCR

honored to be chairing a session  in this track — with none other than Terry Kenakin  on the speaker lineup Hearing Terry speak is more than an academic experience — it’s like being handed a new set of tools to pharmacology series where Terry Kenakin breaks down receptor pharmacology, functional selectivity, and ligand scientists, biotech leaders, CRO professionals, and investors from around the globe meet Boston’s vibrant life GPCR ecosystem. 📅 September 24, 2025 📍 Pressed Café, Huntington Ave, Boston ⏰ 6–8 PM EST ⚠️ Space is limited

. 🚨 First-ever Live AMA with Dr. trafficking, and dynamics—if your probes preserve function, minimize phototoxicity, and work in both live This applied article walks through ligand-directed labeling, SNAP/Halo tags, and fluorescent ligands practical guidance on TR-FRET compatibility, photobleaching resistance, and 3D stack acquisition for tissue-like Physiological relevance:  Fluorescent ligands can retain receptor integrity—critical when signaling readouts

Without the right model, it’s like staring at identical twins—you can’t tell them apart until you see The shift continues linearly. Allosteric? The shift plateaus once the allosteric site saturates. You add a non-radioactive analog of a ligand, expecting it to displace binding. Without a framework, this looks like an assay error. a shift,” “seems like baseline activation”—you’re leaving risk on the table.

But for Ajay Yekkirala, that closed door lit the fuse for a career that would reimagine GPCR therapeutics His work spans deep academic research, startup life, and the application of machine learning and pharmacology that slow down or prevent good science from reaching patients — particularly in underfunded fields like of progress in structural biology and pharmacology, predicting how  a GPCR will respond to a given ligand In August 2025, Superluminal Medicines announced a collaboration with Eli Lilly and Company to advance

Terry's Corner – Curve Shifts Don’t Lie, But Your Eyes Might In early drug discovery, “those curves look practical framework to validate differences, confirm subtle shifts, and benchmark your results against literature Validate with confidence:  Benchmark your results against literature standards and confirm whether your Premium Members get a 50%+ discount when they join Terry’s Corner. 🚨 First-ever Live AMA with Dr. Listen to the whole conversation ➤ GPCR Happy Hour – Boston, September 2025 Space is limited.

Space is limited. Big ideas aren’t. The most valuable conversations don’t happen under fluorescent lights — they happen when the ties are Scientists, investors, and CRO professionals fly in from around the world, while Boston’s own vibrant life Axxam’s capabilities span the full spectrum of GPCR families, including aminergic, peptide, lipid, and on Huntington Ave in Boston 📅 Date:  September 24, 2025 ⏰ Time:  6-8 pm EST 👥 Capacity:  Space is limited

excelling in the PCAT and gaining admission to pharmacy school at the University of Michigan, it seemed like I realized in that moment that I didn't want to be a pharmacist but I had tailored four years of my life bulb moment where I felt for the first time in my life, I understood why people pursued a PhD. That project was her lightbulb moment. In life and career, taking risks can lead to personal and professional growth.

impair breathing, why xylazine complicates interventions, and how receptor-level insights can save lives Like many young scientists, she explored different paths and gained industry experience before realizing While writing a literature review on opioid and alcohol addiction susceptibility, something shifted. The work no longer felt like an assignment—it felt like a calling. “I really like academia.

Breakthroughs this week: Novo Nordisk cuts Ozempic® cost; Nxera launches obesity pipeline; Superluminal–Lilly Discover how factors like restricted tissue diffusion and receptor density can dramatically alter drug Listen now to understand how two mechanisms intersect—and why pharmacologists are critical in addressing Why contribute: Join a global, like-minded GPCR community.

If you’re applying orthosteric logic to modulator-driven systems, you’re likely misreading your assays—and You’ll learn how to recognize these shifts using vivid analogies (like Bruce Wayne vs. Kenakin shows how even small cooperativity values (like α = 0.1) cap the shift in signal . Switch cell lines. Add G protein. Suddenly, the agonist works . The takeaway:  what looks like pharmacology failure may be a systems problem .

and then conjugated with a fluorescent ligand. Fluorescent ligands provide real-time data on receptor activation, ligand binding and downstream signaling using live-imaging modalities. The dashed line represents the frontier between both cell types. Fluorescent ligands: Bringing light to emerging GPCR paradigms.

Katerina Leftheris’ talk, which talked about new and innovative technologies used to overcome peptides limitations Sharing the round table discussion with these excellent scientists felt like a dream come true, and Maria given targeted both traditional GPCRs such as the serotoninergic receptor 5HT1A, but also newer targets like Xiaoyu Zhang showed great insight into new ligands for new E3 ligases for PROTAC development.

During that project we tested its validity as a fluorescent probe for Tag-lite® assays, where we used a set of 7 cannabinoid ligands (both natural and synthetic) to validate and optimize the assay. Because Tag-lite® is based on FRET, we have collaborated with BMG Labtech to develop an application note In this case, Terbium is used as donor and CELT-335 fluorescent ligand is used as acceptor. FSX is the ideal microplate reader for characterizing the GPCR-ligand interactions.

In this case, we would like to focus on the synthesis of fluorescent probes. has several advantages: it is usually very robust, good yields, reagents are found in most chem labs (like Not only do they work in aqueous medium, but also in aprotic solvents like DMF, where you will need to Thanks to the unique linker structure we obtain, which can be divided into three differentiated parts It also poses some disadvantages – just like acid-amine amide coupling, some byproducts are obtained

I’ve lived this firsthand, not just in theory, but by building these systems from the ground up.

In This Session, You’ll Gain: ✅ Modeling tools to understand how restricted diffusion  in tissues like Kenakin walks through cases where two equipotent ligands produce radically different clinical outcomes And when receptors are dense (like GPCRs on membranes), this rebinding hits the collisional limit , where Why Half-Life Can Lie to You Most teams use systemic half-life as a proxy for action. Terry Kenakin Monthly Ask‑Me‑Anything sessions with live Q&A An expanding on‑demand library for novices

—Alessandro Nicoli This two-way growth has turned mentoring into one of his favorite parts of PhD life

Watch Episode 171 What happens when your protein has no known ligands, no structure, and very little The Problem: Hundreds of Receptors, Almost No Ligands Alessandro’s work focuses on olfactory GPCRs—nearly Most have only one known ligand, if any. That meant simulations, ligand screening, and experimental design could move forward with confidence. More accurate hypotheses, faster ligand discovery, and new strategies to tackle one of biology’s most

At first glance, when a ligand appears to bind at two different affinities in the same system, it seems It’s common to observe two apparent affinities for a ligand under certain experimental conditions. In many systems, a ligand may appear to bind with very high affinity when it facilitates formation of ligand-receptor-G protein complexes —an observation that creates the illusion of multiple sites.   Without appreciating their limitations, it’s easy to misinterpret affinity values, potentially leading

Same Affinity, Different Outcomes: Why Residence Time Matters More Two ligands. balance between lipid and aqueous environments.   And while orthosteric ligands may never reach them, properly designed intracellular drugs can. Persistent binding isn’t just about longer half-lives—it’s about smarter pharmacology. Terry Kenakin Monthly Ask‑Me‑Anything sessions with live Q&A An expanding on‑demand library of past lessons

more nuanced, and mastering drug binding kinetics is essential for pipeline efficiency: How fast a ligand Competitive conditions —such as the presence of endogenous ligands— change kinetic behavior , and ignoring Kinetic measurements reveal hidden liabilities or advantages that static affinity numbers cannot. How do competing ligands slow or alter binding rates, and what does this tell you about real-world pharmacology Without appreciating their limitations, it’s easy to misinterpret key kinetic signals that matter for

Listen Now – Real Lessons from a GPCR Expert ➤ The future of GPCR isn’t waiting.

CRCM Must-read publications : AlphaFold3 benchmarking for GPCRs; new structural insights into peptide ligand At first glance, when a ligand binds at two different affinities in the same system, it seems logical If you’re not accounting for their limitations today, your team risks costly misinterpretations that Katerina Leftheris : New technologies overcoming peptide limitations with insights from both pharma and and team fit—not just credentials Design workflows that enable curiosity-driven research Support work-life