Jon Fay and David Farrens
If you’re a vertebrate animal, you should be interested in new findings from the Farrens lab. All vertebrates use G protein-coupled receptors (GPCRs) to detect a variety of different stimuli. Upon binding their target molecules, these membrane proteins undergo structural changes that induce internal signal transduction cascades and alter cellular responses. Because GPCRs are involved in so many signaling systems and diseases, they are a common drug target in pharmacology.
Recently, two exciting new areas of GPCR research have emerged. The first revolves around the discovery that GPCR activity can be modulated by allosteric ligands. These allosteric drugs bind at sites completely different from where traditional GPCR drugs are known to bind. The second new area involves the discovery that GPCRs are surprisingly flexible and often play more than one role in the cell. For example, sometimes different drugs can bind at the same spot on a GPCR, yet activate different signaling pathways. The latter process, called “biased signaling,” can occur for drugs binding in the traditional “pocket” in the receptor, as well as for allosteric ligands. Understanding how both these phenomena occur is of great therapeutic interest. New allosteric ligands that can preferentially induce biased signaling for one pathway versus another hold promise as a powerful way to complement the effect of existing pharmaceuticals, further dial in GPCR responses, and optimize the beneficial aspects of existing drugs while minimizing negative side-effects.
Precisely how allosteric ligands could induce biased signaling behavior is not known. However, a new paper by Jonathan Fay, Ph.D., and David Farrens, Ph.D., has begun to address this question by looking at the structural biology of the receptor.
G protein-coupled receptors are intrinsically dynamic proteins that serve as conduits for disseminating information across the cell membrane. Here, a fluorescent probe, bimane (green), was attached to the human cannabinoid receptor (blue) to identify conformational fluctuations that occur in the receptor (purple haze) upon binding small molecule ligands that bind to the traditional binding site (aqua) as well as allosterically (white).
Their study, “Structural dynamics and energetics underlying allosteric inactivation of the cannabinoid receptor CB1,” published in the July 7, edition of PNAS, discovered that a new structure is induced in the marijuana receptor (called CB1) by an unusual allosteric ligand, Org 27569. They found that while Org 27569 causes CB1 to bind more activating drugs (cannabinoid agonists), at the same time it inhibits the receptors’ ability to activate G-protein signaling. Intriguingly, their results indicate that the binding of Org 27569 induces a new structure in the CB1 receptor, one that is biased towards other signaling pathways. Based on their findings, they proposed that this new structural state may be something that can universally occur in other GPCRs, thus affecting their signaling pathways as well.
These findings about the cannabinoid receptor are especially interesting, as they indicate that this receptor—which is common across multiple species—can be affected by multiple drugs binding at different sites. Together, these results indicate the potential for developing new pharmaceuticals that can complement, not compete with, cannabinoids, thus channeling signaling in directions that would be more beneficial for patients and cannabinoid enthusiasts.
This study was funded by NIH Training Grant T32 DA007267 (to J.F.F.) and NIH Grants R01 EY015436 and S10 RR025684 (to D.L.F.). David Farrens is an associate professor and Jonathan Fay is a senior post-doc in the School of Medicine Department of Biochemistry and Molecular Biology at OHSU.