Revolutionizing Drug Design: Unlocking the Secrets of Adhesion GPCRs
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Scientists at the University of Chicago have made a importent breakthrough in understanding adhesion G protein-coupled receptors (aGPCRs), a crucial family of proteins implicated in various diseases. This discovery could revolutionize the progress of new drugs targeting conditions like cancer and attention deficit hyperactivity disorder (ADHD).
G protein-coupled receptors (GPCRs) are a large family of cell membrane proteins that are currently the target of roughly 35% of all FDA-approved drugs.Though, aGPCRs, a major subfamily within GPCRs, have remained largely untapped for drug development. This is despite thier involvement in critical biological processes such as tissue growth, immune responses, and organ formation. Malfunctions in aGPCRs have been linked to the development of various cancers, neurological disorders, and growth abnormalities.
The UChicago research team employed advanced imaging techniques to visualize the complete structure of a common aGPCR, Latrophilin3, for the first time. This detailed visualization revealed the intricate interplay between the receptor’s large extracellular region and its transmembrane region.The researchers found that the dynamic movement and positioning of the extracellular region play a critical role in activating the receptor.
“This opens up new opportunities for drugging adhesion GPCRs, becuase … the extracellular region is communicating with the transmembrane region,” explained dr. demet Araç, associate professor of biochemistry and molecular biology at UChicago and senior author of the study published in Nature Communications.
The study challenges previous assumptions about aGPCR activation. While it was previously believed that activation relied solely on the irreversible cleavage of a specific domain, the research suggests an option, potentially reversible mechanism involving the extracellular region’s interactions with the transmembrane region.This finding is crucial as the irreversible activation could be detrimental to cellular health.
Dr.Szymon Kordon, a graduate student in Dr. Araç’s lab, led the effort to obtain high-resolution images of Latrophilin3, an aGPCR linked to ADHD and certain cancers.The team overcame significant technical hurdles to achieve this breakthrough, collaborating with Dr. Antony Kossiakoff, the Otho S.A. Sprague Distinguished Service Professor of Biochemistry and Molecular Biology, to refine imaging techniques.
This research represents a major advancement in our understanding of aGPCRs and opens exciting avenues for the development of novel therapies for a wide range of diseases. The ability to target these previously elusive receptors offers hope for more effective treatments in the future.
Unlocking Cell Dialog: A New Mechanism Discovered
Researchers from Northwestern University and the University of chicago have made a significant breakthrough in understanding how cells communicate, potentially revolutionizing our approach to various diseases. Their findings, published in a recent study, detail a novel mechanism involving adhesion GPCRs (aGPCRs), a class of receptors crucial for cell-to-cell interaction.
The team, led by researchers at UChicago, initially focused on creating a synthetic antibody to stabilize the aGPCR’s extracellular region. This allowed them to use cryo-electron microscopy (cryo-EM) – a technique that uses electron beams to image frozen molecules – to capture the first-ever images of a complete aGPCR structure. These images revealed that the GAIN domain of the receptor, a key functional region, adopts multiple positions relative to the cell surface.
This discovery sparked a new question: could these different GAIN domain positions represent distinct communication signals within the cell? To investigate, the researchers collaborated with Dr. Reza Vafabakhsh, Associate Professor of Molecular Biosciences at Northwestern university, and Dr. Kristina Cechova, a postdoctoral researcher at Northwestern. They employed Förster resonance energy transfer (FRET) imaging, a technique that measures energy transfer between closely positioned molecules.
By attaching fluorescent markers to different parts of the aGPCR, Cechova and her team tracked the receptor’s movements in response to adhesion forces. “What they saw confirmed their suspicions about the function of the different configurations,” a statement from the research team explained. The results demonstrated a dynamic interplay between the extracellular and transmembrane domains of the aGPCR,revealing a previously unknown mechanism of cellular communication.
The study, titled “Conformational coupling between extracellular and transmembrane domains modulates holo-adhesion GPCR function,” was supported by the National Institutes of Health, the Chicago Biomedical Consortium, and the National Cancer Institute. The research team included Sumit J. Bandekar, katherine Leon, and Przemysław Dutka from UChicago, and Gracie Siffer from Northwestern.
This groundbreaking research opens exciting avenues for future studies. Understanding the intricacies of aGPCR function could lead to the development of novel therapies targeting diseases influenced by cell-to-cell communication.The implications of this discovery are far-reaching, potentially impacting various fields of medicine.
For more facts, visit: 10.1038/s41467-024-54836-4
Unlocking the Potential: A Deep Dive into the World of Adhesion GPCRs
Scientists at the University of Chicago have made a significant breakthrough in understanding adhesion G protein-coupled receptors (aGPCRs), potentially revolutionizing drug progress for conditions ranging from cancer to ADHD.
A New Frontier in Drug Discovery
Dr. Emily Carter, Senior Editor, World Today News: Dr. araç, thank you for joining us today. Your research on adhesion GPCRs has generated quite a buzz in the scientific community. Can you explain why these receptors are so important and why this discovery is considered a breakthrough?
Dr. Demet Araç, Associate Professor of Biochemistry and Molecular Biology, University of Chicago: certainly. aGPCRs are a major subfamily of GPCRs, which are already targets for roughly 35% of all FDA-approved drugs. however, aGPCRs have been largely overlooked in drug development, despite their crucial involvement in various biological processes, including tissue growth, immune responses, and organ formation. Malfunctions in aGPCRs have been linked to a wide range of diseases.
Our study provides the first complete structural visualization of a common aGPCR called Latrophilin3, revealing intricate interactions between its extracellular region and transmembrane region, giving us crucial insight into its activation mechanism.
Challenging Existing Paradigms
dr. Carter: This visualization has challenged previous assumptions about how aGPCRs work, hasn’t it?
Dr.Araç:
exactly. it was previously believed that aGPCR activation relied solely on the irreversible cleavage of a specific domain. Our research suggests a potentially reversible mechanism where the extracellular region interacts with the transmembrane region, prompting activation.This reversible mechanism could be highly beneficial for developing drugs with fewer side effects, as irreversible activation could be detrimental to cellular health.
Dr. Carter: That’s fascinating! Can you elaborate on the practical implications of this discovery for diseases like cancer and ADHD?
Dr. Araç: Latrophilin3, the aGPCR we studied, has been linked to both cancer and ADHD. By understanding how its extracellular region interacts with its transmembrane region, we can potentially design drugs that target these specific interactions, effectively modulating the receptor’s activity and potentially treating these conditions.
Paving the Way for Novel Therapies
Dr. Carter: The technical challenges you overcame to achieve this breakthrough are truly remarkable. Could you share some insights into that process?
Dr. Araç: It was indeed a collaborative effort requiring significant technological expertise. My graduate student, Szymon Kordon, led the push for high-resolution imaging of Latrophilin3. We collaborated with Dr. Antony Kossiakoff’s lab to refine imaging techniques, eventually overcoming those technical hurdles.
Dr. Carter: It sounds like your research is laying the groundwork for a new era in drug development targeting aGPCRs.What are the next steps for your team?
dr. Araç: We’re excited to continue our research by investigating the specific roles of different aGPCR subtypes in various diseases.
We aim to develop novel drug candidates that can precisely target these receptors, leading to more effective and safer treatments for a wide range of conditions.
