Researchers at the Stanford University School of Medicine have taken an early step toward identifying a new approach to drug discovery that may eventually yield drugs with fewer side effects.
In a study to be published online Jan. 7 in Nature, investigators led by senior author Brian Kobilka, MD, professor and chair of molecular and cellular physiology, found that largely neglected regions on key cell-surface proteins undergo minute changes in shape in response to drugs and thus could prove useful in drug design. The study's first author is Michael Bokoch, an MD/PhD student in Kobilka's laboratory.
The class of proteins known as G-protein-coupled receptors, or GPCRs, is already immensely important in drug research, accounting for some 40 percent of all currently marketed drugs, said Kobilka. His laboratory focuses on a particular type of GPCR called adrenergic receptors, which are activated by adrenaline and its close cousin noradrenaline. Secreted by the adrenal glands and certain nerve cells, these two "molecules on a mission" regulate key physiological actions in the central nervous system, heart and musculature. They are acclaimed for tripping off the "fight or flight" response, which steels middle-aged mortals' melting muscles for high-stakes activities like fending off saber-tooth tigers or running to catch a bus.
Like all GPCRs, an adrenergic receptor consists of three portions. One is anchored within a cell's outer membrane. The second juts from the cell's outer membrane surface and is exposed to the external environment. And the third extends into the cell's fluid interior, or cytoplasm.
Cell-surface receptors are akin to customized doorbells that ring only if pressed by molecular fingers with precisely the right shape. For an adrenergic receptor, the fingers with the magic touch are adrenaline and noradrenaline. When a molecule of one of these structurally similar substances happens upon an adrenergic receptor, it is drawn to a site on the receptor called a binding pocket with just the right shape and charge for a snug fit. (An adrenergic receptor's binding pocket sits within the portion of the receptor that is anchored in the cell's outer membrane.) The binding event alters the shape (or "conformation") of the receptor's cytoplasm-facing domain, setting off a massive redirection of activity inside the cell.
Other molecules besides adrenaline and noradrenaline can slip into adrenergic receptors' binding pockets. That's the basis for many effective drugs. Cell-surface receptors are great targets for the small molecules that drug developers discover and deliver into our bodies to stimulate or shut down a physiological process. Various drugs can affect the same receptor quite differently. "Agonists" lock their targeted receptor into an active or even hyperactive mode. "Antagonists" force the receptor into a sluggish or inactive posture so that it stalls out, or they simply get in the way of the naturally occurring molecules the receptor was meant to match.
Adrenergic receptors come in nine different varieties, or subtypes, all responsive to adrenaline and noradrenaline but playing different roles in regulating bodily functions. For instance, Kobilka said, the beta-2 adrenergic receptor is the chief regulator of smooth muscle, especially in relaxing air passages such as the lungs (a fight-or-flight necessity). This makes beta-2 agonists, which open airways, good for combating an asthma attack.
It is primarily the beta-1 receptor that accelerates the heartbeat and stimulates the heart to pump more blood per beat. That's also great for a fight-or-flight response. But too much beta-1 stimulation over an extended period can lead to medical problems like heart failure. Thus, beta-1 antagonists (also known as beta-blockers) are often prescribed for patients with coronary artery disease, heart failure or arrhythmias.