Search Results

“Academia is about knowing when to walk and when to run.” Imposter Syndrome and Finding Your Place Ben shares the moment he realized he mattered, when he was A Final Aha Moment: Try the Crazy Idea When a collaborator offered a neuroma model (one where opioids

Some breakthroughs don’t start with a hypothesis. They start with a sentence that freezes the room. I can image the whole islet. Not a single cell, not a cropped region, not a patch of fluorescence — the entire pancreatic islet , 100–200 microns across, lighting up in real time. That moment didn’t just validate a probe. It opened a new window into GPCR imaging in native tissue, and reshaped what this collaboration between a chemist and a biologist could make possible. The Moment GPCR Imaging Became a Turning Point Before the islet lit up, the collaboration wasn’t even aimed at imaging. Johannes “JB” Broichhagen trained as a synthetic chemist — someone who trusted carbon–carbon bonds far more than live-cell behavior. Yet curiosity and chemistry pulled him into the world of GLP-1R, pancreatic β-cells, and the biological questions David Hodson had been exploring for years. The call from David — the glowing islet — created a pivot the team couldn’t ignore. A fluorescent peptide probe binding with clarity and specificity was exciting enough. Seeing that probe expose receptor distribution across an entire native islet changed what they believed was possible. This was more than data. It was ignition. A single successful GPCR imaging experiment can transform a project’s trajectory. From that moment, imaging wasn’t an add-on. It became the center of gravity. How a Chemical Design Sparked a GPCR Imaging Breakthrough The concept was elegant: antibodies weren’t delivering reliable GLP-1R visualization. A ligand-based peptide probe could, offer the consistency and surface selectivity GPCR imaging demands. One issue: JB had never made peptides Solution: collaborate. Working with a peptide specialist at the Max Planck Institute, the team moved quickly from concept to synthesis. What emerged was more than a ligand — it was a tool that enabled reproducible, stable, and high-contrast GPCR imaging across cells and tissue. Once the first images came in, the scientific questions multiplied: Could the probe support super-resolution GPCR imaging? Could they map receptor heterogeneity across the islet? Could they quantify plasma membrane vs. intracellular receptor pools? Could these tools scale to multiple GPCRs? The design didn't just work — it revealed. Interdisciplinary design isn’t optional in GPCR imaging. It’s the catalyst. The breakthrough didn’t happen because the chemistry was perfect. It happened because the chemistry and the biology met in the right way. The Human Reaction Behind a GPCR Imaging Milestone Scientists rarely talk about the emotional side of discovery — the instant where the experiment stops being data and starts being meaning. JB describes early experiences vividly: Seeing calcium waves flicker in cells. Realizing tissue is alive, unpredictable, and full of hidden structure. Feeling the urge to take phone pictures of super-resolution data and send them to collaborators because he couldn’t keep the excitement to himself. That same emotional imprint hit with the whole-islet image. It wasn’t just successful GPCR imaging — it was proof that receptors could be seen as they truly exist in native tissue, not simplified models. GPCR imaging doesn’t just visualize receptors. It gives scientists a way to feel the biology. This emotional spark carried the team through the next steps — validation, iteration, and expanding the scope of what these probes could do. Why Chemical Probes Shift the GPCR Imaging Landscape Chemical probes don’t replace antibodies outright — but they excel where antibodies struggle. For GPCR imaging, their strengths are practical and decisive: Consistency from batch to batch Long-term stability Compatibility with live cells and intact tissue Surface-receptor specificity A compact footprint that fits sub-10 nm resolution techniques These attributes enable experiments that previously required compromise. And the most striking validation came from in vivo GPCR imaging. Two-photon microscopy revealed a glowing islet in a living mouse — a moment JB calls the “Holy Grail” of chemical biology. Better GPCR imaging doesn’t just capture biology — it expands the biological questions the field can ask. The tools didn’t simply visualize receptors. They unlocked pharmacologically relevant insights that were previously inaccessible. The Collaboration Model That Makes GPCR Imaging Possible Behind every technical advance in this story sits something less tangible but equally decisive: a collaboration grounded in trust and fun. That’s how JB describes it — and it’s exactly why the work moved quickly. He learned tissue complexity from David; David picked up the quirks of acetonitrile. They exchanged instincts as much as data, and built a shared rhythm of problem-solving. Strong GPCR imaging tools come from strong interdisciplinary relationships. Good collaborations share protocols. Great collaborations share momentum. The trust between chemistry and biology drove the project forward faster than either discipline could have moved alone. Where GPCR Imaging Goes Next Once the breakthrough happened, the horizon widened dramatically. JB’s team now moves GPCR imaging toward: New fluorophores engineered for deep-tissue clarity Multi-color strategies for parallel receptor mapping Super-resolution imaging of receptor nanodomains AI-assisted probe design Multi-receptor visualization in complex tissue The dream is ambitious and increasingly feasible: A catalog where scientists choose a receptor, choose a color, and visualize biology exactly as it exists — in cells, in tissue, in living organisms. Not one receptor at a time. Not one color. Not one imaging depth. The islet lighting up wasn’t the pinnacle. It was the proof of concept. GPCR imaging is evolving from a specialized technique into a foundational method for receptor biology. And this breakthrough became one of the stepping-stones. This conversation is part of a three episode series produced in collaboration with our partners at Celtarys Research . If this behind-the-scenes story resonated, you’ll love the full conversation.  🎧 Listen to the full episode https://www.ecosystem.drgpcr.com/dr-gpcr-podcast/chemical-probes-for-gpcr-imaging-and-internalization If JB's story resonates 🎧 Listen to part 1 of this series with Dr. David Hodson

But everything changed when his recurring pain — and the rigid protocols around opioid prescription — "When you talk to patients that have an unmet need, you learn things that no one is thinking about in

But Sokhom Pin stayed loyal to GPCRs , even when big pharma turned its gaze to other targets like kinases

What initially appears mechanistically clear can become more nuanced when additional experiments are Pharmacologists know the pressure of distinguishing between orthosteric and allosteric drug mechanisms—especially when When a system approaches full allosteric occupancy, the Schild plot curves and the slope falls below This “tissue volume control” becomes essential when: Distinguishing affinity-dominant from efficacy-dominant

It is about building a team that can operate when clarity is missing. When those conditions hold, skill-based hiring looks smart. When they do not, it starts to fail quietly. It also changes what questions matter when building the team. Usually, when the science refuses to cooperate.

October 2022 β-arrestin1 and 2 exhibit distinct phosphorylation-dependent conformations when coupling advanced NanoLuc/FlAsH-based biosensors reveals distinct conformational signatures of β-arrestin1 and 2 when

coupled receptors under diverse states Fan Liu , Han Zhou , Xiaonong Li , Liangliang Zhou , Chungong Yu

Schlander M, Hernandez-Villafuerte K, Cheng CY, Mestre-Ferrandiz J, Baumann M. Shen S, Zhao C, Wu C, Sun S, Li Z, Yan W, et al. J Phys Chem B. 2016;120(11):2878-85. 36.         J Biol Chem. 2018;293(19):7466-7473. 45.         Teng X, Chen S, Wang Q, Chen Z, Wang X, Huang N, et al.

This combined with the use of polarized light leads to a signal that can only be detected when the fluorescent When polarized light hits a free fluorescent ligand, its rotation speed is so fast that the emission On the other hand, when the polarized light hits the bound fluorescent ligand, the slower rotation speed Adapted from: Zhang Y, Tang H, Chen W, Zhang J. ACS Med Chem Lett. 2022 Jan 10;13(2):243-249. doi: 10.1021/acsmedchemlett.1c00598.

This method has several advantages: it is usually very robust, good yields, reagents are found in most chem Chem.   2016 , 59  (10), 4443–4458. https://doi.org/10.1021/acs.jmedchem.5b01409 . Bioconjugate Chem.   2015 , 26  (1), 145–152. https://doi.org/10.1021/bc5005262 . Chem. Rev.   2008 , 108  (8), 2952–3015. https://doi.org/10.1021/cr0783479 .

and subsequent activation of the G-protein heterotrimeric complex (α, β, and γ); it is at this point when Liu-Chen, and J.R. J Biol Chem, 2009. 284(27): p. 18357-67. https://pubmed.ncbi.nlm.nih.gov/19416973/ 5.

Through developing a high-resolution method, Hao Chen et al. directly visualized the fusion of vesicles Chen, X. Zhang, and L. Ma. 2008.

Binding Assays The best saturation curves of the seven fluorescent ligands were obtained in C5aR Chem Specific binding of the most promising fluorescent antagonists in Chem 1 cell lines. The signal in C5aR transfected Chem-1 is compared with the untransfected parent cell line to study fluorescent EC50 affinities obtained by flow cytometry saturation binding experiments in C5aR transfected Chem-1 Chem.

this has the potential to enhance GPCR subtype-selectivity, it also presents a significant challenge when modulators (NAMs), that fully or partially dampen the receptor's functional response to the ligand (Wold, Chen selectivity, which can arise from greater sequence variation in allosteric sites among receptor subtypes when This is particularly important when dealing with receptor subtypes that exhibit significant similarity substantial doses of allosteric modulators with a diminished risk of target-related toxicity (Wold, Chen

determined to be 30.1 ± 1.7 nM corresponding to apparent Ki ± SEM = 15.7 ± 0.9 nM according to the Cheng-Prusoff Chem.   2022 , 65  (6), 4832–4853. https://doi.org/10.1021/acs.jmedchem.1c02033 . (18)      Dempsey, C.; Chen, K. H.; Bates, M.; Zhuang, X.

J Biol Chem, 2018. 293(19): p. 7466-7473. 8.      Nat Chem Biol, 2020. 16(8): p. 841-849. 10.    J Biol Chem, 2007. 282(14): p. 10576-84. 13.   

activation initiates conformational changes, exposing an intracellular cavity (Kang, Y. et al. 2015, Chen F et al. 2021, Chen, H. et al. 2022).

What happens when a GPCR is activated? When the endogenous binder of the GPCR (which can be a neuromodulator, neurotransmitter, etc.), binds Chem Rev. 2017 Jan 11;117(1):139-155. Studying these routes may reduce side-effects when using GPCR-based therapies. drug development targeting CNS diseases , especially as traditional targets seem to have stagnated when

Hauser Calcineurin-fusion facilitates cryo-EM structure determination of a Family A GPCR Jun Xu , Geng Chen

This can be appreciated when talking about SCRAs (Synthetic Cannabinoid Agonists), as one of the series Chem.   2019 , 62  (1), 276–287. https://doi.org/10.1021/acs.jmedchem.8b00368 . (9)         Adams, A. Chem. Bioconjugate Chem. 2013 , 24  (11), 1907–1916. https://doi.org/10.1021/bc400328m . (16)      Morrison Chem.   2006 , 49  (1), 70–79. https://doi.org/10.1021/jm050467q .

Norton Cheng and Dr.

was the most common method for predicting G protein-coupled receptor (GPCR) structures, especially when antipsychotic-like effects in rodent models, reinforcing the value of AlphaFold in drug discovery, especially when Nat Chem Biol   7 , 769-778 (2011).   https://doi.org/10.1038/nchembio.662 Diaz-Holguin, A.  

When it comes to signal transduction, cellular context matters. Pharmaceuticals (Basel, Switzerland), 14(5), 439. https://doi.org/10.3390/ph14050439 Chen, K.

Dysfunction of the adhesion GPCR latrophilin 1 (ADGRL1/LPHN1) increases the risk of obesity Norton Cheng

When I started studying aGPCRs, the structural conformation of the GAIN domain of ADGRL1/Lphn1 and ADGRB3 of human ADGRL3-G13, this paper reports that the stalk peptide of ADGRL3 adopts a hook conformation when Furthermore, when an alignment analysis of the Stalk peptide of the aGPCR family was performed highlighted ., Zhu, X., Wang, N., Xu, Z., Xia, R., Liang, J., Duan, Y., Yin, H., Xiong, Y., Zhang, A., Guo, C., Chen

Ki values were then calculated using the Cheng–Prusoff equation, with CELT-331 parameters fully reported When medicinal chemists evaluate affinity jumps between analogues, image data can help resolve questions

Chem Rev, 2017. 117 (1): p. 111-138.

When the distance between donor and acceptor is close enough, energy is transferred, and a second, short-lived This is moreso the case when detecting partial agonism or weak receptor interactions. By using two labeled ligands the transference of energy event will only happen when the adequate distance Curr Chem Genomics. 2009 May 28;3:22-32. doi: 10.2174/1875397300903010022.

When comparing the CKRs structures complexes, the disulfide bridges formed between the N-loop and the agonist (maraviroc) (Tan, Zhu et al. 2013, Zheng, Han et al. 2017, Isaikina, Tsai et al. 2021, Zhang, Chen CCL15L (residues 26-92) and CCL15M (residues 27-92), while the third structure lacks a ligand (Shao, Shen conformational change of Y2917.43 tilted toward TM2, a model supported by mutagenesis experiments (Shao, Shen