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Bryan Roth joins the Dr. GPCR community live this week to examine what happens when GPCR selectivity is encoded not at the receptor, but at the receptor–transducer interface. T This is one of 12+ live Masterclasses planned for 2026 — all included in Premium, each one a direct scientific exchange with a leading scientist, with full replay access afterward. Also this week: Terry Hébert previews his April 16 session on iPSC-derived translational models, and a new podcast episode with Joseph Kim on GPCR structural biology and drug discovery at opioid and galanin receptors. GPCR Selectivity: Allosteric Modulators as Intracellular Molecular Glues Standard models attribute signaling specificity to ligand-stabilized receptor conformations — a framework that does not fully account for selectivity that can also emerge from receptor–transducer complex stabilization. SBI-553 at NTSR1 and PCO371 at PTH1R illustrate how intracellular modulators engage cytoplasmic interfaces directly, stabilizing specific receptor–transducer assemblies across GPCR families A, B, and T. This session with Bryan Roth will cover how intracellular modulation controls G protein and arrestin coupling — and whether the molecular glue framing offers a productive framework for targeting gain- and loss-of-function diseases. In 48h: April 9, 2026, 10 AM EST Join the live discussion ➤ This live session with recording available as well as all masterclasses are now included in Premium. Not a member yet? Explore the Dr. GPCR University iPSC-Derived Systems for GPCR Signaling and Translation HEK293 systems are powerful tools for pharmacological screening, but they have a structural limitation when signaling outcomes depend on cell type, signaling complex assembly, and disease biology. Terry Hébert's upcoming session examines how patient-derived induced pluripotent stem cells (iPSCs), organoid systems, and biosensor-based assays extend GPCR pharmacology into disease-relevant environments, with dilated cardiomyopathy as a concrete model system. Next week: April 16, 2026, 10 AM EST. Join the live discussion ➤   This live session with recording available as well as all masterclasses are now included in Premium. Not a member yet? Explore the Dr. GPCR University Terry's Corner AMA — How Important Is It to Know Where Your Molecule Binds? Whether a molecule binds at the orthosteric or allosteric site determines its pharmacological behavior entirely. An orthosteric compound hijacks the target and imposes its own efficacy. An allosteric compound works in concert with endogenous signaling, producing a different pattern entirely. In this live AMA, Terry Kenakin will the methods that differentiate these binding modes and why this distinction carries practical consequences for drug discovery programs at any stage. Thursday, April 16, 1:00 PM ET  — note the adjusted time. Send us your questions ahead of time at Terry@DrGPCR.org Free for Kenakin Brief subscribers. Sign up to get access ➤ Dr. Joseph Kim: Structural Biology and Drug Discovery at GPCRs Cryo-EM has transformed how we visualize receptor–ligand interactions — and with it, how we think about drug discovery at GPCRs. In this episode, Joseph Kim, a postdoctoral scholar in Ashish Manglik's lab at UCSF, discusses structural studies of opioid receptors, the challenge of peptide-binding GPCRs, and why understudied receptors like the galanin family may be worth revisiting with today's tools. One small molecule studied in the Manglik lab interacts with both the μ- and κ-opioid receptors, acting differently at each — a concrete illustration of how receptor-specific pharmacology complicates drug discovery and why structural insights matter. Listen now ➤ Quick Links GPCR Antibody Validation in Real Systems  → Request GeneTex samples Biased Signaling Microcircuits in Drug Discovery  →   Read DiscoverX article A2A Fluorescent Competitive Binding with NanoBRET®  → Explore assay approach This Week's Scientific Highlight Binder2030: a quantitative membrane proteome binding dataset enabling AI-driven drug discovery Membrane proteins represent more than half of therapeutic targets but remain underrepresented in quantitative ligand-binding datasets. Binder2030 addresses this gap — a curated affinity selection-mass spectrometry dataset comprising 3,384 small-molecule ligands across approximately 400 transmembrane proteins, including GPCRs, SLC transporters, and ion channels. Standardized Kd measurements enable comparative analysis of affinity distributions and chemical space across target classes, with downstream integration demonstrated in a structure-based modeling workflow comparing Boltz-2 predicted potencies with experimental affinities for a GlyT-1 ligand set. From the Masterclass Library This week's featured course from the Masterclass Library: Unconventional GPCR Ligands with Terry Kenakin . Classic hormones and small molecules no longer capture the full complexity of GPCR targeting. This course examines prodrugs, biologics, irreversible inhibitors, and molecular glues — and how these unconventional ligand classes address long-standing challenges in selectivity, efficacy, and clinical translation. Explore the library ➤ What Members Say The Dr. GPCR community is where scientists connect — across disciplines, across career stages, across the science. "Thank you so very much for having me on the podcast. I really enjoyed our conversation. You made it a very comfortable and engaging experience, and I appreciate how you thoughtfully guided our chat. It felt like we were chatting over coffee — and hoping this becomes a reality in the future." — Anita Nivedha, Computational Chemist About Dr. GPCR Dr. GPCR is the intelligence and community platform for GPCR scientists. Premium members access the full Masterclass library, weekly curated publications, live sessions, and the Terry's Corner AMA series. This Week in Premium Premium Members are reading 15 new publications this week, including a quantitative membrane proteome binding dataset enabling AI-driven drug discovery. Plus 6 industry updates and 1 new Masterclass recording now available — Purinergic GPCR Ligand Design with Kenneth Jacobson and Matteo Pavan. Explore Premium ➞

GPCR Allosteric Modulators as Novel Intracellular Molecular Glues Classic models explain biased signaling through ligands that stabilize receptor conformations and favor selective transducer interactions. This Masterclass with Bryan Roth will examine an additional mechanism: intracellular modulators that bind directly at receptor–transducer interfaces. Examples such as SBI-553 at NTSR1 and PCO371 at PTH1R , already characterized, provide concrete cases where ligands engage both receptor and transducer. SBI-553 functions as a PAM-agonist for arrestin while modulating G protein engagement through direct interaction with NTSR1 and Gαo. PCO371 promotes G protein signaling while inhibiting arrestin recruitment through intracellular binding. These systems are used here as resolved examples of how interface binding can stabilize specific signaling complexes alongside receptor conformation-based mechanisms. Key implications: SBI-553 illustrates how arrestin signaling can be stabilized through direct receptor–Gαo interface engagement rather than distal conformational effects. PCO371 shows that G protein bias can be achieved through intracellular binding that suppresses arrestin recruitment at PTH1R. Interface-directed ligands introduce a second control layer for selectivity alongside receptor conformations. Join us live, April 9, 2026, 10 am EST. This live session with recording available as well as all masterclasses are now included in Premium. Reserve your spot ➤ iPSC-Derived Systems for GPCR Signaling and Translation Heterologous systems such as HEK293 cells enable scalable pharmacological assays, but they simplify the cellular context in which GPCR signaling occurs. This limitation affects how signaling data can be interpreted when receptor behavior depends on cell type, signaling complex assembly, and disease biology. This session with Terry Hébert will examine how iPSC-derived cardiomyocytes , organoid systems , and biosensor-based assays extend GPCR pharmacology into more physiologically relevant environments. iPSC-derived cardiomyocytes allow signaling to be studied in disease contexts such as dilated cardiomyopathy. Organoid systems introduce multicellular organization, while biosensor-based approaches enable direct monitoring of signaling pathways within these systems. Key implications: iPSC-derived cardiomyocytes reveal GPCR signaling behaviors that differ from HEK293-based systems, particularly in disease-relevant contexts. Organoid models incorporate cellular architecture that affects receptor signaling and pathway integration. Biosensor-based assays enable direct measurement of signaling dynamics within complex biological systems. Join us live, April 16, 2026, 10 am EST. This live session with recording available as well as all masterclasses are now included in Premium. Reserve your spot ➤ GPCR Pharmacology: Open Problems and Discussion Binding assays and functional assays are often treated as complementary readouts of the same interaction. This framework has a structural limitation: binding measures the receptor population that engages tracer ligands, while functional assays measure the receptor population that couples to signaling pathways. This AMA will discuss how these formats diverge, particularly for allosteric ligands, where efficacy can change without measurable shifts in affinity. Key implications: Binding and function probe different receptor populations, so discrepancies are expected rather than anomalous. Allosteric modulators can alter signaling efficacy without changing ligand affinity, uncoupling binding readouts from functional outcomes. Interpreting mode of action requires aligning assay format with the specific receptor state being measured. March 26, 12 pm EST. Access provided via newsletter signup. Sign up to the Kenakin Brief Newsletter ➤ Quick Links Antibody validation continues to constrain GPCR targeting and reagent confidence. Read article ➤ Biased signaling can also be framed as circuit-level organization rather than binary switching. Read analysis ➤ Computational descriptions of ligand bias remain central to linking structural motion with signaling selectivity. Listen now ➤ GPCR signaling also controls insect behaviors such as blood feeding and mating in ways that broaden how receptor biology is studied. Explore discussion ➤ This Week’s Scientific Highlight GPR61, implicated in appetite and body weight regulation, is inhibited by inverse agonists that bind an induced intracellular allosteric pocket, disrupting receptor–G protein interactions and abolishing constitutive activity through a direct interface mechanism. From the Masterclass Library Premium Members also have access to Decoding Drug Action with Dr. Kenakin — a course that defines affinity, efficacy, orthosteric versus allosteric binding, and kinetics as the four parameters required to interpret GPCR ligand behavior across assay systems. It's the kind of clarity that changes how you read your own data. Explore the library ➤ What Members Say “Dr. Hoare's extensive and elaborative explanation of the topics at hand was excellent and very digestible. Thoroughly enjoyed learning from him.” This Week in Premium This is what Premium Members are reading this week: 20 classified papers including one on GPR61 inverse agonists acting at an intracellular allosteric pocket, 9 contributor articles , 14 industry news and 7 events . Not a Premium Member Yet? Join the ecosystem ➤ About Dr. GPCR Dr. GPCR brings together scientists working across GPCR biology, pharmacology, and drug discovery to examine how signaling mechanisms are measured and applied. Premium membership includes live masterclasses, full replays, and access to the complete Masterclass Library, alongside curated research and industry updates.

The Cell Surface Is Only Part of the Story For decades, GPCR pharmacology centered on events at the cell membrane. A ligand binds, a G protein couples, a second messenger is produced, and the receptor internalizes to terminate the signal. This framework shaped how assays were designed, how drug candidates were profiled, and how efficacy was understood. But the receptor’s journey does not end at internalization. Work on receptors such as GLP-1R and MC4R has demonstrated that internalized GPCRs can continue to signal from within the endosome, generating sustained responses that diverge from what the cell-surface interaction alone would predict. Whether a receptor recycles back to the membrane or is degraded inside the cell depends on the ligand–receptor complex — and that distinction has direct implications for therapeutic duration, efficacy, and safety. Not Just Agonists: Antagonists Internalize Receptors Too One of the foundational assumptions in receptor pharmacology was that internalization required agonist-driven activation. That assumption does not hold universally. Studies on MC4R show that both the agonist alpha-MSH and the antagonist AgRP drive receptor internalization. The receptor does not require a classical agonist-induced conformational change to leave the cell surface — it requires an active state, and antagonists can produce one. This finding reframes how internalization data should be interpreted. If antagonist-occupied receptors also traffic away from the membrane, then surface receptor counts cannot be used as a simple readout of agonist activity. The model needs to account for the possibility that both arms of the pharmacological response — activation and inhibition — alter receptor availability. Endosomal Signaling: A Second Source of Response GLP-1 provides a striking example of why internalization cannot be equated with signal termination. When GLP-1 binds its receptor, the complex internalizes — but cyclic AMP production continues for hours beyond what the initial surface interaction would sustain. The internalized receptor signals from within the endosome, creating a second source of second messenger production. This behavior is agonist-dependent. At the MC4 receptor, alpha-MSH–driven responses can be washed off and antagonized by AgRP — these are cell-surface events. Melanotan II, acting at the same receptor, produces a response that resists washout and antagonism, because the signaling complex has moved inside the cell and is no longer accessible to surface-acting agents. The same receptor, the same second messenger, but two fundamentally different pharmacological profiles depending on the ligand. Beta-Arrestin as Gatekeeper: Core Versus Tail Beta-arrestin mediates the transition from surface to cytosol, and its own conformational state encodes what happens next. Two established conformations — the core conformation and the tail conformation — direct the receptor toward different fates. Core-conformation binding routes the receptor toward endosomal degradation. Tail-conformation binding favors rapid recycling back to the cell surface. BRET-based assays can quantify beta-arrestin recruitment and, depending on the assay design, distinguish between these conformational outcomes. Knockdown studies confirm the dependency: in cells where beta-arrestin expression is reduced, receptor internalization is substantially inhibited. This positions beta-arrestin not simply as a trafficking partner, but as the molecular switch that determines whether the receptor’s intracellular journey is temporary or terminal. Recycling Versus Degradation: The CCR5 Example The therapeutic stakes of this distinction are illustrated by chemokine receptor CCR5 in the context of HIV entry. RANTES rapidly internalizes CCR5, but the receptor recycles back to the surface just as quickly — offering only transient protection against viral entry. The analog AOP-RANTES also internalizes CCR5, but drives the receptor toward degradation rather than recycling. The result is sustained receptor depletion and meaningfully improved protection. What separates these two outcomes is the ligand-induced receptor active state. The same receptor, the same internalization machinery, but the conformational code written by the ligand determines whether the cell replenishes its surface receptors or loses them. Experimentally, this steady state between recycling and degradation can be dissected by blocking one pathway — for example, using a cell-surface antagonist to reveal the recycling kinetics that would otherwise be masked. Measuring GPCR Internalization: Assay Strategies Beyond Imaging The classical approach to detecting internalization has been imaging — visualizing receptor redistribution as punctate intracellular structures. While direct and intuitive, imaging is limited in throughput and quantification. Alternative approaches offer complementary advantages. Loss of cell-surface signal from tagged receptors provides a quantitative, non-imaging measure of internalization. Diffusion-enhanced resonance energy transfer extends this further by capturing both internalization and recycling as the receptor re-emerges and re-engages with labeled ligand in the medium. Pharmacological tools such as Dynasore — a GTPase inhibitor of dynamin 1 and 2 — block internalization entirely, isolating the endosomal contribution to the total response. And judicious tag placement on endosomal markers, rather than the receptor itself, allows detection of internalization without modifying the receptor — preserving native trafficking behavior. Why Terry’s Corner Receptor internalization is not a single event — it is a branching process where the ligand, the receptor active state, and the arrestin conformation together determine the pharmacological outcome. Standard assays capture the initial step, but the frameworks that connect internalization to recycling, degradation, and sustained endosomal signaling require a more structured approach. This is the kind of problem Terry’s Corner was built for. Dr. Terry Kenakin’s session on measuring GPCR internalization walks through the assay logic, the mechanistic distinctions, and the interpretive frameworks that connect trafficking data to therapeutic decisions. It is part of a structured environment where pharmacologists sharpen their thinking on exactly these questions — with Terry in the room. 🟢 40 years of expertise at your fingertips: Explore the complete library ➤ ✳️ Want to know what’s inside? Read the latest articles ➤ Stay sharp between lectures. Subscribe to The Kenakin Brief today ➤

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Explore the world of GPCRs with Dr. GPCR Podcast! Join industry leaders as they share insights, stories, and groundbreaking discoveries, enriching our understanding of GPCRs. Delve into the science behind these vital components shaping our collective knowledge. Welcome to the Dr. GPCR Podcast - The Voice of the Community Conversations with the world’s leading GPCR scientists. Exploring discoveries, careers, and ideas shaping human health. In each episode, we sit down with leading experts to explore their career journeys, groundbreaking discoveries, and the impact of their research on our shared understanding of GPCR biology. Launched at the height of the pandemic, the Dr. GPCR Podcast was created with three goals: Share discoveries – Highlight the latest advances in the GPCR field. Amplify voices – Provide scientists a platform to showcase their work. Inspire the future – Motivate the next generation to pursue GPCR research. At its core, Dr. GPCR’s mission is simple yet ambitious: to bring the GPCR community together - across borders and disciplines - to connect, exchange, and collaborate in order to improve human health through a deeper understanding of GPCR biology. Latest Podcast Episodes More podcast episodes Dr. GPCR Podcast Audience Survey We are currently planning our next season and need your help. This short survey will help us understand your needs to bring you exciting and informative content. We also know that you are busy, which is why we designed this short survey that should take you 5 minutes. Fill out this form Be our Guest In each episode, we chat with an expert about their career trajectory, discoveries, and how their research contributed to the shared pool of knowledge about GPCR biology. We’d love to have you on our podcast. To be a guest, fill out the form below, and we’ll be in touch in 48 hours. Fill out this form What others are saying about this podcast "You made it a very comfortable and engaging experience, and it felt like we were chatting over coffee — Yamina thoughtfully guided our chat throughout." Anita Nivedha I think it's really well done. I'm genuinely interested to see how it evolves and grows over time, as I feel it has the potential to develop into something even more impactful. Anonymous This came at just the most perfect time. I hadn't heard a scientific talk outside my lab since February and was starved to hear someone else talk passionately about GPCRs. I've listened to the episodes multiple times and it's just like being at a conference getting new ideas. I just couldn't be happier y'all created this podcast. Anonymous Great initiative, thanks. Carrier paths, choosing research topics, switching fields, late start, failures and successes. Anonymous I enjoy the breadth of questioning that goes beyond just the science, and reveals a bit about the scientists as individuals/mentors/people. Anonymous Really enjoyable science podcast! Dr. Yamina Berchiche interviews leading GPCR scientists on this vibrant, entertaining podcast. I really appreciate the way the podcast educates and mentors, particularly towards junior scientists but also to the community as a wholen Yamina is a great interviewer, getting insight and personal history from her guests. Am very grateful for Dr GPCR livening up the week in these difficult times! Sam @Pharmamechanic Listen and subscribe where you get your podcasts

Browse 380+ GPCR resources — Masterclasses, podcasts, Weekly News, jobs, and events — searchable by topic, scientist, and type. The most comprehensive knowledge system in GPCR science. Intelligence Hub Every resource the GPCR ecosystem has ever produced. Searchable by topic, scientist, and type. The most comprehensive knowledge system in GPCR science — browse the full scope of what exists. 380+ Resources - 85 Masterclass sessions - 120+ Podcast episodes - 48 Scientists featured Filter by: Scientific Category Scientists Type April 7, 2026 Measuring GPCR Internalization Explore the assays and frameworks for measuring GPCR internalization — from beta-arrestin gating to endosomal signaling, recycling, and degradation. A structured session inside Terry’s Corner by Dr. Terry Kenakin. Terry Kenakin 🔒 Watch Course April 7, 2026 Olfactory Receptor Activation Reduces Platelet Reactivity and Arterial Thrombosis Through Actin Cytoskeleton Remodeling Study targeting orphan platelet GPCR OR2L13 as novel antithrombotic strategy; high-throughput screen identified non-odorant compounds that reduce platelet reactivity via actin cytoskeleton remodeling. 🔒 Read Publication April 7, 2026 GPCR Internalization: When the Signal Moves Inside the Cell GPCR internalization does not end signaling — it redirects it. This article explores the assays, beta-arrestin gating mechanisms, and recycling-versus-degradation frameworks that determine receptor fate inside the cell. Terry's Desk Read the Article April 7, 2026 GPCR Selectivity Beyond the Receptor — Live April 9th with Bryan Roth Bryan Roth joins the Dr. GPCR community live this week to examine what standard models don't account for — what happens when GPCR selectivity is encoded at the receptor–transducer interface rather than the receptor alone. Yamina Berchiche Read the Article April 6, 2026 The Expanding Landscape of the Glucagon Signaling Network: mechanisms and outcomes Review of glucagon signaling mechanisms beyond glycemic control, covering effects on amino acid, lipid, and energy metabolism, with implications for glucagon-based pharmacotherapy. 🔒 Read Publication April 5, 2026 Structural determinants for GPCR-mediated inhibition of TASK K2P channels by diacylglycerol and its dysfunction in disease Reveals structural and molecular mechanisms underlying GqPCR regulation of TASK K2P channels via DAG binding, explaining pathogenic effects linked to K2P channelopathies. 🔒 Read Publication April 4, 2026 ROS disrupt COP9 signalosome-mediated ABCA1 protection and trigger its ubiquitination and degradation by cullin3 inhibiting cholesterol efflux and promoting foam cell formation in response to GPCR agonists Reveals xanthine oxidase-dependent H2O2 role in GPCR agonist-induced ABCA1 destabilization via COP9 signalosome disruption and cullin3-mediated ubiquitination, promoting foam cell formation. 🔒 Read Publication April 3, 2026 Lilly to acquire Centessa Pharmaceuticals to advance treatments for sleep-wake disorders 🔒 Read the News April 3, 2026 Updated: Lilly wins FDA approval of anti-obesity pill orforglipron, setting up new battle with Novo 🔒 Read the News April 2, 2026 The multifaceted roles of G protein-coupled receptor C3aR1 in disease: From immunomodulation to cancer progression 🔒 Read Publication April 2, 2026 Zealand Pharma Establishes U.S. Research Hub in Cambridge, Massachusetts to Expand Drug Discovery Capabilities and Accelerate Medicine Creation 🔒 Read the News April 2, 2026 Binder2030: a quantitative membrane proteome binding dataset enabling AI-driven drug discovery 🔒 Read Publication 1 2 3 4 5 1 ... 1 2 3 4 5 6 7 8 9 10 11 12 13 ... 13 You can see everything. Premium lets you access it. $499/year for the most comprehensive GPCR knowledge system in the field. Every resource above — and everything added going forward — is yours. Start Your 14-Day Trial - $50 Full access for 14 days. Then $499/year to continue.