Nobel chemistry: pharma directions

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Not two years since spectroscopyNOW reported on the work of Brian Kobilka of Stanford University School of Medicine and has won a Nobel Prize jointly with Robert Lefkowitz of the Howard Hughes Medical Institute and Duke University Medical Center, Durham, North Carolina, USA, for studies of G-protein-coupled receptors.

G-protein-coupled receptors are involved in the mode of action of almost half of all prescription medications and so represent an obviously important area of study for improving our understanding of current pharmaceuticals, explaining side-effects, and of course developing future treatments for a wide range of diseases.

The GPCRs can be seen to act as a modular system that allows cells to transmit a wide variety of signals across their membranes, to other cells and over long distances in the body. These proteins mediate a flow of information that tells the inside of cells about external conditions. Understanding such processes at the molecular level has often built on X-ray crystallographic structures of the species involved as well as protein nuclear magnetic resonance (NMR) spectroscopy.

Lefkowitz used radioactive iodine tracers in 1968 to investigate cell hormone receptors and uncovered the beta-adrenergic receptor. The team achieved its next big step during the 1980s. Along with new recruit Kobilka, they isolated the gene. That research showed how the receptor was similar to light-sensitive receptors in the eye. Lefkowitz and his co-workers Andre De Lean and Jeffery Stadel thus developed a generalised model of receptor activation, which is referred to as the ternary complex model.

The ternary complex involves the transmembrane GPCR, the extracellular ligand (the agonist), and the intracellular G-protein, which serves as the activated signalling unit. The agonist might be a hormone, such as adrenalin, a neurotransmitter including dopamine and serotonin, an odorant molecule or some other chemical stimulus, which hints at just why so many pharmaceuticals rely on this receptor system given the vast range of agonists one might envisage all with different functions.

It took three decades for the details to be laid bare so that we now have a much clearer understanding of how trans-membrane signalling by GPCRs occurs. In what the Nobel committee describes as a "crowning achievement", Kobilka and his co-workers obtained a three-dimensional structure of a fully functional ternary complex at high resolution. Specifically: the beta2-adrenergic receptor in complex with agonist and G-protein. The receptor is modulated by the fight or flight hormone, adrenalin, and its chemical cousin, noradrenalin.

Nobel underpinnings

As spectroscopyNOW reported at the time, the researchers used NMR spectroscopy, with heteronuclear single-quantum coherence (HSQC) and saturation transfer differencing (STD)-filtered H-detected heteronuclear multiple-quantum coherence (HMQC) pulse sequences, to look at one specific part of the beta-2 adrenergic receptor's extracellular domain. In subsequent work, the Kobilka team built on their work to finally acquire a structure for the receptor at the moment when it transfers the signal from the hormone on the outside of the cell to the G-protein on the inside of the cell.