G-protein-coupled receptors (GPCRs) are a large family of proteins that span cell membranes. They sense molecules outside the cell and activate a signalling pathway within. GPCRs respond to a range of stimuli including well-known signalling molecules such as hormones and neurotransmitters (making them extremely important drug targets), as well as other triggers such as light, flavour and odour. The work of Robert J. Lefkowitz at the Howard Hughes Medical Institute and Duke University, and Brian K. Kobilka at Stanford University, has uncovered a wealth of information about the structure of GPCRs and how they work. Now Lefkowitz and Kobilka have been awarded the 2012 Nobel Prize in Chemistry in recognition of their contributions to this field of research.

Credit: © 2011 NPG

In the 1960s, scientists knew about the signalling effect of hormones such as adrenaline, but the nature of the receptors they interacted with remained a mystery. Lefkowitz and colleagues used radioactivity to trace several cell receptors and investigate their biochemistry — including the β-adrenergic receptor, which is activated by adrenaline. In the 1980s, Lefkowitz and his research group, which now included Kobilka, managed to purify enough of the β-adrenergic receptor to sequence it and clone the gene that encodes for it. When they analysed the gene they discovered a similarity to another gene that encodes for a receptor in the eye that responds to light. Lefkowitz and the team realized that these receptors formed a family — one that is now known as GPCRs.

As scientists started to understand more about the biochemistry of GPCRs, Kobilka focused on determining their three-dimensional structures. In 2007, Kobilka and his collaborators solved the structure of the β-adrenergic receptor — only the second reported structure for a GPCR. In 2011 they went one further when Kobilka and co-workers obtained the structure (pictured) of the activated β-adrenergic receptor (green) bound to an agonist (yellow spheres), and coupled to the associated G-proteins (gold, cyan and purple).