About the collaborative
The G Protein-Coupled Receptor (GPCR) Collaborative, launched in 2023, aims to unravel the mysteries of these vital membrane proteins that profoundly impact human health and disease. These receptors govern various cellular functions and physiology, making them a prime target for a significant number of FDA-approved drugs. The objective of the GPCR Collaborative is to achieve groundbreaking, mechanistic insights into GPCR physiology by leveraging cutting-edge technologies. A key strategy will be to shift the focus from studying average properties of molecules to understanding the properties and functions of individual molecules and assemblies in space and time. The collaborative team will integrate and improve advanced methodologies such as time-resolved single-molecule imaging, cryo-electron microscopy (cryoEM), proximity labeling, experimental and virtual compound screens, computational structural biology, and data science. By exploring new frontiers in single-molecule imaging and combining it with ensemble-scale experiments, the research seeks to unveil the structural and kinetic frameworks underlying GPCR signaling, G protein and arrestin activation and downstream partner interactions. This mechanistic understanding will pave the way for developing innovative strategies to regulate GPCR activation and signaling bias using small molecules and peptides, ultimately leading to more effective patient care approaches.
Although most GPCR-targeting drugs act through the orthosteric binding site (which endogenous agonists bind to), there is a clear need and therapeutic potential for non-orthosteric binding site ligands. Currently, only one biased and two allosteric compounds have received FDA approval.
The collaborative team is specifically focused on advancing initiatives beyond the orthosteric site to identify positive allosteric modulators (PAMs) and negative allosteric modulators (NAMs) that engage various receptor sites to amplify the response elicited by orthosteric ligands. These binders can influence and potentiate signaling pathway selectivity.
Scott Blanchard, PhD
Pioneering work by the Lefkowitz lab has demonstrated the potential of PAMs and NAMs in achieving greater specificity and fine-tuning receptor signaling by potentiating or inhibiting the effects of endogenous agonists.
While PAMs and NAMs have been identified for GPCRs and G proteins, their mechanisms of action have yet to be fully elucidated, and this area remains relatively underdeveloped and underexplored. Currently, no known compounds directly modulate arrestins, but the Lefkowitz lab has recently identified the first small-molecule modulators of arrestin functions. Scientists expect the discovery of new and effective strategies to directly modulate arrestins' physiological activities to greatly benefit mechanistic studies and enable development of therapeutic interventions using these novel modulators.
M. Madan Babu, PhD, FRS, FMedSci
The projects led by Collaborative members Nobel laureate Robert Lefkowitz, MD, and M. Madan Babu, PhD, FRS, FMedSci, aim to bridge this gap by developing new high-throughput screens, and exploring the direct modulation of arrestin functions using small molecules.
Projects led by Scott Blanchard, PhD, Georgios Skiniotis, PhD, Jonathan Javitch, MD, PhD, and Alice Ting, PhD, will explore the molecular basis of arrestin signaling by structural and kinetic dissection. The Skiniotis and Blanchard labs will investigate the integrated structural and kinetic mechanisms of receptor and signaling partner activation, which will be further examined in cellular contexts through projects in the Javitch and Ting labs. The researchers will rigorously test the structure-function relationships and mechanistic predictions through investigations exploring the activities of newly developed compositions of matter within the Babu and Lefkowitz labs' projects. The molecular insights obtained through these investigations, combined with the synergistic efforts in computational structural biology and data science within the Babu lab, will be instrumental in developing more efficacious and specific therapeutic interventions for human diseases.
Together, the GPCR Collaborative team is at the forefront of GPCR research, where the molecular determinants of GPCR-mediated signal transduction and bias are framed in the context of principled targeting mechanisms that consider time-dependent changes in receptor location, conformation and composition in both healthy and diseased states.
Collaborative members
Lead: Scott Blanchard, PhD – St. Jude Children’s Research Hospital
M. Madan Babu, PhD, FRSC, FMedSci, FRS – St. Jude Children’s Research Hospital
Jonathan Javitch, MD, PhD – Columbia University
Robert Lefkowitz, MD – Duke University
Georgios Skiniotis, PhD – Stanford University
Alice Ting, PhD – Stanford University