Image from the RCSB PDB (www.pdb.org) of PDB ID: 3SN6
Crystal structure of the beta2 adrenergic receptor-Gs protein complex.
How does a cell use its cell? Specifically, how does it pick up signals from the outside world, such as tastes or flavors or sights; or communicate with mobile messengers from inside the body, such hormones and neurotransmitters?
One of the cell's primary means of picking up such signals is a set of proteins (molecular machines) called G-protein-coupled-receptors (GPCRs). The structure of these essential proteins has recently been revealed thanks to the incredible persistence of a soft-spoken researcher and an assist from the Advanced Photon Source (APS), an incredibly bright light source at the Office of Science's Argonne National Laboratory.
Dr. Brian Kobilka of Stanford University has spent much of his professional career studying GPCRs. They're one of the cell's vital communications devices, picking up signals from outside the cell and then telling the cell what to do about them via chemical cascades. Knowing the specific structure of GPCRs could suggest ways to modify the signals they receive or the cellular changes they effect – it could point to potent new medicines that improve their functions. In fact, many of the 800 or so human GPCRs are already targets of between 33 and 50 percent of drugs.
Unfortunately, it's also extremely difficult to determine the exact structure of GPCRs, since they sit right within the cell's membrane, threading in and out of it seven times. To get the structure, scientists have to extract the GPCRs from the cell, stabilize them, and then crystallize them. That's what Dr. Kobilka and his colleagues struggled to do…for more than two decades.
Earlier this year, Dr. Kobilka and his team finally produced a crystal of a GPCR together with its G-protein actually caught in the act of signaling. (For a more detailed look at his long quest, go to: http://www.nature.com/news/2011/110824/full/476387a.html.) They then took those precious crystals to Argonne Lab's APS for analysis. The APS creates the brightest storage-ring generated X-ray beams in the Western Hemisphere, and uses them to divine the detailed structure of minuscule but important objects, such as GPCRs.
Image courtesy of Argonne National Laboratory
The Advanced Photon Source produces some of the brightest X-rays in the Western Hemisphere. X-rays are accelerated to over 99% of the speed of light around its ring, which is the size of a baseball stadium. Over 3,500 scientists from around the world visit the APS every year to do scientific research, which has resulted in over 10,000 published studies and contributed to the 2009 Nobel Prize in Chemistry.
Through the APS, Dr. Kobilka and his team produced the first set of images of a GPCR, specifically, the member of the GPCR family that is activated by the cellular signalers adrenaline and noradrenaline. They then showed the same protein in its active state of signaling, a discovery which was published this past July in the online edition of Nature magazine.
This discovery could have both an immediate and lasting impact. Adrenaline receptors are responsible for the fight-or-flight response, the rapid breathing and heart-beating that accompanies seriously scary and sometimes expensive situations, such as skydiving or any activity that starts with the adjective “extreme.” As a consequence, seeing the structure of this GPCR could suggest new targets for anti-asthma drugs. But since there are so many GPCRs, and because of their unique place in cellular signaling, the APS imaging could open a whole new world of potential medicines.
The success is a signal of the possibilities offered by Office of Science. The individuals who serve there and use its facilities are dedicated to seeing basic research address some of the most pressing challenges of our time. It's a unique call to action, one the persistent efforts of Dr. Kobilka and his team have recently answered by imaging the structure of a cellular cell.
For more information on Argonne Lab and its APS, please go to: http://www.anl.gov/. And for more information on DOE's Office of Science, please go to: http://science.energy.gov/.
Charles Rousseaux is a Senior Writer in the Office of Science.