The Chemistry Behind the 2012 Nobel Prize

The Official Website of the Nobel Prize (www.nobelprize.org) gives little insight into the far reaching importance of Brian Kobilka and Robert Lefkowitz’s work. It states only that the awarding of the Nobel Prize for Chemistry 2012 was: “for studies of G-protein-coupled receptors”.

The two Americans’ innovative work has given us a better understanding of how dramatic changes within the cell can occur in response to a small number of extracellular molecules. It explains the body’s reactions to smells, sights and flavours that are thought to be integral to the functioning of around 40% of current pharmaceutical drugs.

For both scientists, the prize is a culmination of over 20 years’ study of an individual transmembrane protein and throughout this time, the project battled funding setbacks. The level of trial and error that was required reflects not only the difficulty of the research but also Kobilka’s and Lefkowitz’s determination. For Kobilka, this was all to achieve one image, using x-ray crystallography, showing a G-protein-coupled receptor poised to activate a G-protein.

A G-protein-coupled receptor is situated across a cell membrane and works when an extracellular molecule binds to it. This in turn activates a G-protein within the cell which binds to target proteins further inside the cell. The resulting intracellular signalling cascade allows the cell to respond to molecules outside it.

It could be said that Lefkowitz is the master in this area of research, but the real driving force behind the project came from Kobilka, a professor at Stanford University in California. In an interview with The Guardian, he conveyed his hope that this discovery would be “translate[d] … into safer [and] more effective drugs”. He also believes that the research could lead to better “economically developed” drugs, since a greater knowledge of the receptor’s structure has the potential to drive down the price of drug trials.

A real breakthrough came for Kobilka in 2007 when he and his team successfully imaged a G-protein-coupled receptor in high resolution. However, it took another 5 years before the truly desired image of a receptor bound to a corresponding G-protein was obtained. In order to do this, a fatty scaffold (developed at the Scripps Research Institute in California) held the receptor in place while a floppy intracellular loop that threatened the integrity of the protein was held in place by the binding of a T4 lysozyme.

These steps helped lead to crystals which were suitable for x-ray diffraction and provided an image of the receptor–protein complex at the desired resolution of 3.2 Å. At this resolution, one can see the extracellular bound ligand and the bound G-protein at the point activation. Lefkowitz and Kobilka’s triumph will surely be a turning point in medical science.

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