Brian Kobilka, MD, scrutinizes how cells receive the signals we need to send
"Basic research like this can lead to drugs that benefit us all, but NIH funding for it is limited. We often have very bright people with very good ideas who can’t pursue them.”
- Brian Kobilka, MD
“A molecular masterpiece.” That’s how the Nobel committee described the image that earned Brian Kobilka and his colleagues the 2012 Nobel Prize in Chemistry.
After more than 20 years of herculean effort, Brian, who is the Hélène Irwin Fagan Chair in Cardiology, did what many thought impossible. He and his team took an atomic snapshot of a G-protein coupled receptor, just as it transmitted a signal.
G-protein coupled receptors (GPCRs) are molecular complexes embedded in the outer membranes of cells. Tiny relay stations, they receive chemical signals from outside the cell and transmit them inside. GPCRs are the largest class of cellular receptors, and nearly half of all drugs target them.
The GPCR Brian’s team captured in the now-famous image on the opposite page is the ß2 adrenergic receptor, which transmits signals from adrenaline and noradrenaline hormones. A target for asthma drugs, it triggers the “fightor-flight” reflex that accelerates heart rate and opens airways.
Even though GPCRs play a central role in a staggering number of life’s processes, we’ve never been able to see them in action on an molecular scale. Now, thanks to Brian’s tenacity, we have an exquisitely detailed 3-D picture we can use, along with computer modelling, to design better drugs.
But getting that picture wasn’t easy. First, large amounts of the receptor had to be produced via recombinant DNA. Then it had to be purified, locked in its “on” position, and crystallized before being bombarded with X-rays from hundreds of angles. Finally, like re-creating a sculpture from only its shadows, the image had to be extrapolated from all the diffraction patterns the X-rays produced as they hit the crystals.
It wasn’t cheap, either. Just one tiny bottle of the special detergent they needed to purify a week’s worth of receptor cost $1,000. They ran out of funding twice, and at one point, Brian offered to cut his salary just so they could keep going.
Then, out of the blue, a friend called and asked about their progress. Brian told him they were close, but almost out of money. His friend, who understood the project’s potential, donated $300,000, no strings attached. Along with several smaller gifts, this relatively modest infusion of unrestricted funds allowed Brian and his team to finally succeed.
As Brian says, this kind of flexible funding means you can “take that extra shot,” when tackling a difficult problem. For Brian, it meant he could look failure in the face and still keep his eyes on the prize.