Two biochemists won the Nobel Prize in Chemistry today for their studies of G-protein-coupled receptors (GPCR), an important class of membrane proteins involved in cell signalling and disease, making them an important drug target.
“I’m thinking this is going to be a very, very hectic day,” Lefkowitz said by telephone during a press conference earlier today. “I was going to get a haircut, which if you could see me is quite a necessity, but I’m afraid that’ll have to be postponed.”
GPCRs are a large family of membrane proteins consisting of about 1000 members that initiate cell responses by sensing exterior environmental conditions. These proteins bind to a wide variety of large and small ligands that are involved with many cellular processes from visual and olfactory sensory perception to neurotransmission.
In a paper published by the Proceedings of the National Academy of Sciences in 1982, Lefkowitz reported that his group had isolated one of the most common GPCRs, beta-2 adrenergic receptor (ADRB2), that binds to epinephrine to regulate the fight-or-flight response (1). He then went on to isolate and determine the amino acid sequences of several subtypes of adrenergic receptors, leading to the realization that GPCRs share a similar structure. Since then, Lefkowitz has also discovered protein families that make GPCRs resistant to drugs.
During the 1980s, Kobilka began studying ADRB2 as a postdoctoral fellow in Lefowitz’s lab at Duke. Then, he went on to Stanford in 1989 where he focused on determining the molecular structure of the ADRB2. In a paper published by Nature in 2011 (2), Kobilka and colleagues reported a crystal structure of ADRB2 that was bound to a ligand, providing a high-resolution view of how the GPCR works.
The future of drug development relies heavily on the understanding of how these GPCRs work. Since a protein’s function is dependent on its structure, structural biologists continue to strive to be the first to solve further GPCR structures.
But Kobilka tries not to focus on that. “Scientists are sometimes as competitive as professional athletes, maybe. But you can’t worry about it too much, or it will distract you from your goal,” said Kobilka in a telephone interview with Nobel Media. “So, I’m not sure what else to say about that. But if you really want something bad enough, if you’re really interested in something enough, you know, you just keep working on it.”
1. Shorr, R. G., S. L. Heald, P. W. Jeffs, T. N. Lavin, M. W. Strohsacker, R. J. Lefkowitz, and M. G. Caron. 1982. The beta-adrenergic receptor: rapid purification and covalent labeling by photoaffinity crosslinking. Proc Natl Acad Sci USA 79(9):2778-2782.
2. Rasmussen, S. G., B. T. DeVree, Y. Zou, A. C. Kruse, K. Y. Y. Chung, T. S. S. Kobilka, F. S. S. Thian, P. S. S. Chae, E. Pardon, D. Calinski, J. M. Mathiesen, S. T. Shah, J. A. Lyons, M. Caffrey, S. H. Gellman, J. Steyaert, G. Skiniotis, W. I. Weis, R. K. Sunahara, and B. K. Kobilka. 2011. Crystal structure of the β2 adrenergic receptor-Gs protein complex. Nature 477(7366):549-555.