One in every three FDA-approved drugs targets a single superfamily of receptors on human cells, initiating various biochemical pathways to prevent heart attacks or allergic reactions. These receptors are part of the G protein-coupled receptor (GPCR) family and are often associated with accessory proteins known as RAMPs, which play a crucial role in transporting GPCRs to the cell surface and modifying signal transmission. Recognizing the importance of these protein-receptor interactions in drug development, researchers at Rockefeller’s Laboratory of Chemical Biology and Signal Transduction, led by Thomas P. Sakmar, sought to map out the interactions between 215 GPCRs and the three RAMPs they form complexes with.
The study, published in Science Advances, presents a novel approach to studying GPCR-RAMP interactions on a large scale, providing valuable insights into the complex relationships between these receptors and associated proteins. By identifying how RAMPs influence GPCRs and their signaling mechanisms, researchers hope to enhance drug development and potentially explain why some GPCR drugs have failed in the past. This comprehensive map of GPCR-RAMP interactions could also shed light on how orphan GPCRs, whose ligands are still unknown, are activated in the human body.
Creating a comprehensive map of GPCR-RAMP interactions was a challenging task due to the vast number of possible combinations between three RAMPs and nearly 800 GPCRs. To address this challenge, researchers developed an assay in collaboration with the Science for Life Laboratory in Sweden and the Human Protein Atlas Project, allowing for the simultaneous screening of hundreds of GPCR-RAMP interactions in a single experiment. This innovative approach significantly expanded the understanding of GPCR-RAMP interactions and provided a wealth of data that could revolutionize drug development and basic biological research.
The team utilized a combination of antibodies from the Human Protein Atlas and magnetic beads to identify GPCR-RAMP interactions through a color-coding system. By conducting hundreds of experiments at once, researchers were able to track the interactions between 215 GPCRs and the three known RAMPs, generating a vast amount of data in a high-throughput manner. This groundbreaking technology enabled researchers to examine a wide range of GPCR-RAMP complexes simultaneously, offering valuable insights into the roles these interactions play in drug development and biological processes.
The results of the study offer significant resources for GPCR researchers and drug developers, including publicly available libraries of anti-GPCR antibodies, engineered GPCR genes, and detailed maps of GPCR-RAMP interactions. By making these resources accessible online, researchers can easily access information about their favorite receptors, identify binding antibodies, and determine whether a receptor interacts with a RAMP. This comprehensive dataset increases the number of experimentally identified GPCR-RAMP interactions and sets the stage for future techniques that could detect harmful autoantibodies and enhance drug discovery efforts.
Overall, this study represents a major advancement in understanding the complex interactions between GPCRs and RAMPs and their implications for drug development. By providing a comprehensive map of GPCR-RAMP interactions, researchers have unlocked new possibilities for studying GPCR signaling mechanisms, identifying potential drug targets, and developing innovative therapies. This technology-oriented project has the potential to revolutionize the field of drug discovery and pave the way for more effective treatments for a wide range of medical conditions.