The reason we can see, taste and smell, and even why our heart races when we get excited or scared, can be explained by the actions of a family of “gatekeeper” proteins known as G protein-coupled receptors (GPCRs). In fact, GPCRs are the largest family of signalling proteins in the human genome. They are involved in virtually all physiological processes and represent the single largest target class for medicines on the market.
This year’s Nobel Prize in Chemistry has been awarded to a pair of US-based physician researchers, Professor Robert J. Lefkowitz of Duke University, and Professor Brian K. Kobilka of Stanford University, for their fundamental contributions to our understanding of these proteins and their function.
GPCRs are found on the surface of all cells, and their job is to respond to even the subtlest of stimuli from the outside of the cell, be they particles of light, odours or hormones (such as adrenaline, dopamine or serotonin) and transmit them as biological effects on the inside. They do so by changing their shape and interacting with intracellular proteins, in particular the family of “G proteins” (the discovery of which resulted in the award of the Nobel Prize in Medicine to Martin Rodbell and Alfred Gilman in 1994).
Given that GPCRs are the key mediators of information flow from the external environment into cells, it comes as no surprise that decades of research have been expended on understanding how this information flow is achieved; how so many different types of signals can be recognised by a common protein family; how these proteins are regulated in health and disease; and how they can be exploited for novel drug discovery.
So much of what we know about these processes can be traced to the seminal contributions of Lefkowitz and Kobilka.
Robert Lefkowitz was one of the first to develop chemical approaches for directly detecting GPCRs on cell membranes, in particular characterising the receptor target for adrenaline and related hormones. This work facilitated subsequent studies that demonstrated how GPCRs require interaction with G proteins to achieve their effects, and also led to the biochemical isolation and purification of these receptors.
The next major breakthrough came when Brian Kobilka joined Lefkowitz as a post-doctoral researcher, and cloned the gene for the beta-adrenergic receptor, the first GPCR for adrenaline. Comparison of the sequence of this receptor with that of rhodopsin, a receptor in the retina that responds to light and allows us to see, led to the astonishing insight (pardon the pun) that these proteins are structurally related; although their activating molecules are strikingly different, the receptors represented founding members of a huge, hitherto-unappreciated family. Numerous labs subsequently confirmed this with the identification of hundreds of GPCRs over the years.
More recently, attention has turned to how these receptors can be regulated by drugs and by proteins other than their G protein partners. Research has also focused on what molecular mechanisms determine how a stimulant on the outside of the cell can interact with GPCRs to cause changes that are transmitted to the inside of the cell. Lefkowitz has made the major contributions to the former question, while Kobilka to the latter.
The most recent breakthrough came just last year from Kobilka and his co-workers, who solved the high resolution crystal structure of an activated beta-adrenergic receptor in the processes of binding its ligand and its G protein partner; essentially a “snap-shot” of the activation process occurring at the molecular level and a feat described by the Nobel Committee as a “molecular masterpiece”. This allowed, for the first time, an insight into the structural basis of signal transduction by these key proteins at the molecular level.
Why are these findings so important?
The involvement of GPCRs in virtually every biological process and most diseases – including cardiovascular disease, obesity and diabetes, neuropsychiatric disorders, inflammation and cancers – means that GPCRs can provide a fertile ground for chemistry and novel drug discovery. However, this has proven a larger than anticipated challenge due to the lack of detailed information on how these proteins work and how they can be targeted in a manner that avoids side-effects.
For example, how can we activate or block a GPCR for dopamine in one part of the brain without hitting another GPCR that also recognises dopamine in other parts of the body? And why do some chemicals that act at the same GPCR prove clinically effective, but other ones fail? These questions reflect the level of subtlety that can make or break modern drug discovery efforts.
Here at Monash University, we are fortunate to have Brian Kobilka as an Adjunct Professor and close collaborator with our laboratory, which focuses on addressing some of these issues.
More broadly, an understanding of how GPCRs work at the molecular and structural levels can lead to enormous advances in the chemical targeting of these proteins that can yield improvements to human health in a far more timely and cost-effective manner than is currently available.