International Union of Crystallography

Crystal structure determination of G-protein-coupled receptors leads to Nobel Prize

[Brian Kobilka][Robert Lefkowitz]The Nobel Prize in Chemistry for 2012 has been awarded to Robert Lefkowitz (left, Howard Hughes Medical Institute and Duke University Medical Center, Durham, NC, USA) and Brian Kobilka (right, Stanford University School of Medicine, Stanford, CA, USA) for groundbreaking studies of G-protein-coupled receptors (GPCRs).

GPCRs allow the cells to sense their environment and respond to stimuli. They are responsible for many signalling processes, including the regulation of heart rate and blood pressure and the sensations of sight, smell and taste, and about half of all prescription drugs target GPCRs.

The mechanism of action of GPCRs at a molecular level was elucidated using X-ray crystallography. GPCRs are membrane proteins and as such are difficult to crystallize but once this hurdle was overcome the structure of activated receptors was solved and the mechanism revealed.

Former General Secretary and Treasurer of the IUCr and the Chair of the Nobel Committee for Chemistry, Professor Sven Lidin, has commented on the award as follows:

This year's Nobel Prize in chemistry celebrates the elucidation of the details of intercellular signalling. It rewards a number of important discoveries that together have given us an insight into the wonderful world of G-protein coupled receptors. Is this chemistry? Is it not biology or even medicine? The answer is that thanks to scientific contributions such as these, an important part of biology and medicine is chemistry today.

This Prize rewards work that is the natural continuation of the 1962 Nobel Prizes in Physiology or Medicine and in Chemistry. The now iconic structure of the DNA molecule and the groundbreaking work on the structure of globular proteins heralded a new era where structural biology has become an integral part of modern biochemistry.

Crystallography has come a very long way in 50 years, and it is continuously reinventing itself, allowing us to study problems that were unthinkable just a few years ago. Thanks to this development chemistry is becoming more crystallographic, as crystallography has become one of the necessary techniques for all chemists. Simultaneously, crystallography itself is becoming more chemical. The crystallization technique needed to ultimately solve the structure of a ternary complex in its active form is a scientific tour-de-force of unusual proportions. The receptor itself is designed to be flexible and the active complex is designed to be unstable and Brian Kobilka had to use every tool in the box, including several that he invented specifically for this purpose, to achieve crystallization.

For a list of articles on GPCRs published in IUCr journals please click here

A critical development which enabled the crystallographic work on this complex system was the microcrystallography. This enabled samples to be scanned to locate strong diffraction or to find small crystals, as well as data collection strategies to be developed that reduced scattered background and matched the beam to the diffracting volume. These aspects have been reported in the following articles in IUCr Journals:

This Nobel prize is a special occasion for the Synchrotron Radiation community as it marks the 5th Nobel Prize that is associated with Synchrotron Radiation, the first being awarded to John Walker in 1997 on the structure-mechanism of F1-ATPase, a moment that was marked by a special celebratory issue of the Journal of Synchrotron Radiation. It is also a special occasion for the Advanced Photon Source that becomes the first synchrotron to be associated with two Nobel prizes. We note also that the European Synchrotron Radiation Facility played an important role in the early stages contributing to the structure solution of the second GPCR structure after rhodopsin as reported in Nature in 2007.

For more details see the IUCr Nobel Prizewinners page.

Photo credits: (l.) Duke University Photography; (r.) Linda A. Cicero/Stanford News Service.