January 16, 2013 | 1
G Protein-Coupled Receptors (GPCRs) are the messengers of the human body, key proteins whose ubiquitous importance was validated by the 2012 Nobel Prize in chemistry. As I mentioned in a post written after the announcement of the prize, GPCRs are involved in virtually every physiological process you can think of, from sensing colors, flavors and smells to the action of neurotransmitters and hormones. In addition they are of enormous commercial importance, with something like 30% of marketed drugs binding to these proteins and regulating their function. These drugs include everything from antidepressants to blood-pressure lowering medications.
But GPCRs are also notoriously hard to study. They are hard to isolate from their protective lipid cell membrane, hard to crystallize and hard to coax into giving up their molecular secrets. One reason the Nobel Prize was awarded was because the two researchers – Robert Lefkowitz and Brian Kobilka – perfected techniques to isolate, stabilize, crystallize and study these complex proteins. But there’s still a long way to go. There are almost 800 GPCRs, out of which ‘only’ 16 have been crystallized during the past decade or so. In addition all the studied GPCRs are from the so-called Class A family. There’s still five classes left to decipher, and these contain many important receptors including the ones involved in smell. Clearly it’s going to be a long time before we can get a handle on the majority of these important proteins.
Fortunately there’s something important that GPCR researchers have realized; it’s the fact that many of these GPCRs have amino acid sequences that are similar. If you know what experimental conditions work for one protein, perhaps you can use the same conditions for another similar GPCR. Even for dissimilar proteins one can bootstrap based on existing knowledge. Based on the similarity you could also build computer models for related proteins. Finally, you can use a small organic molecule like a drug to essentially serve as a clamp that helps stabilize and crystallize the GPCR.
But all this knowledge represents a distributed body of work, spread over the labs of researchers worldwide and expected to be sequestered by them for their own benefits. These individual researchers working in isolation would not only face an uphill battle in figuring out the right conditions for studying their proteins but would also run the risk of reinventing the wheel and duplicating conditions from other laboratories. The central question asked by all these researchers is, how does the binding of a small molecule like a drug on the outside of a GPCR lead to the transmission of a signal to the inside?
Enter the GPCR Network, a model of collaborative science which promises to serve as a fine blueprint for other similar efforts. The network was created through a funding opportunity from the National Institute of General Medical Sciences in 2010 and has set itself the goal of structurally characterizing 15-25 GPCRs in the next five years. The effort is based at the Scripps Research Institute in La Holla and involves at least a dozen academic and industrial labs.
So how does this network work? The idea for the network came from the recognition that there are hundreds of GPCR researchers spread across the world. Each one is an expert on a particular GPCR but each one has largely worked separately. What the network does is to leverage the expertise from one researcher’s lab and apply it a similar GPCR in another lab (there are technical criteria for defining ‘similarity’ in this case). There are a variety of very useful protocols, ideas and equipment that can be shared between labs. This sharing cuts down on redundant protocols, saves money and accelerates the resolution of new GPCR puzzles much faster than what could be achieved individually.
For instance, a favorite strategy for stabilizing a GPCR involves tagging it with an antibody that essentially holds the protein together. An antibody that worked for one GPCR can be lent to a researcher who is investigating another GPCR with a similar amino acid sequence. Or perhaps there is a chemist who has discovered a new molecule that binds very tightly to a particular receptor. The network would put him in touch with a crystallographer who could use that molecule to fish out that GPCR from a soup of other proteins and crystallize it. Once the crystallographer solves the structure of the protein using this molecule, he or she could then send the structure to a computer modeler who can use it to build a structure for another particularly stubborn GPCR which could not be crystallized. The computer model might explain some unexpected observations from a fellow network researcher who was using a novel instrumental technique. This novel technique would then be shared with everyone else for further studies.
Thus, what has happened here is that the individual pockets of knowledge from a biochemist, organic chemist, crystallographer and computer modeler – none of whom would have proceeded very far by themselves – are merged together to provide an integrated picture of a few important GPCRs. The entire pipeline of protocols including protein isolation, purification, structure determination and modeling also serves as a feedback loop, with insights from one step constantly informing and enriching others. This represents a fine example of how collaborative and open research can accelerate important research and save time and money. It’s to the credit of these scientists that they haven’t held their valuable reagents and techniques close to their chest but are sharing them for everyone’s benefit.
In the three years since it has been up and running, the GPCR Network has leveraged the expertise of many GPCR experts in generating insights into the structure and function of important GPCRs. Its collaborative efforts have resulted in eight protein structures in just two years. These include the adenosine receptor which mediates the effect of caffeine, the opioid receptor which is the target for morphine and the dopamine receptor which binds to dopamine. Every one of these collaborations involved a dozen or so researchers across at least three or four labs, with each lab employing its particular area of expertise. Gratifyingly, there’s also a few industrial labs involved in the efforts and we can hope that this number will increase even as the pharmaceutical industry becomes more collaborative.
It’s also worth noting that the network was funded by the NIGMS, an institution which has been subject to the whims of budget and personnel cuts. This institution is now responsible for an effort that’s not only accelerating research in a fundamental biological area but is also contributing to a better understanding of existing and future drugs. Scientists, politicians and members of the public who are seeking a validation of basic, curiosity-driven scientific research and reasons to fund it shouldn’t have to look for.