October 9, 2012 - By Bruce Goldman
Linda A. Cicero/Stanford News Service
--Brian Kobilka, MD, is a biochemist and chair of molecular and cellular physiology at Stanford University School of Medicine. He holds the Helene Irwin Fagan Chair in Cardiology.
--He grew up in rural Minnesota. His father was a baker, and his mother decorated the cakes.
--Kobilka has devoted most of his career to studying structure and workings of G-protein-coupled receptors, or GPCRs. His research, by vastly improving our understanding of how these receptors work, paves the way for advances in drug design.
--Roughly 800 different GPCRs have been identified to date, making them one of the largest families of human proteins.
--GPCRs, found on cells' outer membranes, all share several common features. Some parts of a GPCR jut out from the outward-facing surface of the cell membrane, while still other parts face inward. The outward-facing components can bind to traveling molecules outside the cell, such as hormones or neurotransmitters (the chemicals used by nerve cells to relay signals to one another).
--When a GPCR binds to a molecule from outside the cell, the shape of the GPCR's inward-facing part undergoes a change in its shape. This, in turn, alters the shape of a so-called "G protein" to which the internal portion of the receptor is closely coupled, triggering one or more cascades of biochemical processes inside the cell.
--Each GPCR has its own characteristic "short list" of molecules to which it binds. The fact that their external surfaces are accessible to small molecules approaching from outside of the cell makes GPCRs ideal drug targets. In fact, as many as one half of all medical drugs target CPCRs.
--During a medical fellowship in the lab of Nobel Prize co-recipient Robert Lefkowitz, MD, at Duke University in the mid-1980s, Kobilka played an instrumental role in determining the exact sequence of a gene for a particular GCPR called the beta-adrenaline receptor. This led to the surprising revelation that the large group of proteins now called GPCRs share common structural features.
--Kobilka has continued to study adrenergic receptors, which among other things regulate the contraction of smooth muscle in the heart, lungs and other organs. Hormones such as adrenaline and noradrenalin activate adrenergic receptors.
--There are nine closely related subtypes of adrenergic receptors, two of which are key to setting off the "fight-or-flight response." One subtype is primarily responsible for elevating blood pressure and accelerating the heartbeat, while the other is mainly responsible for relaxing air passages in the lungs (a fight-or-flight necessity).
--For many years GPCRs had been thought to be too difficult to analyze by X-ray crystallography, which is essential to understanding the three-dimensional shape of large proteins. According to a 2011 Nature article, Kobilka's group became in 2004 the first to crystallize one of the beta-adrenergic receptor subtypes —— a key first step toward determining its structure.
--In 2007, according to the Nature article, his team showed in great detail the structure of this GPCR (the beta-adrenergic receptor) when it is binding to a hormone. In 2011, the article states, he did likewise for the receptor just as it is poised to activate its G-protein, and later that same year he published the first structure of any GPCR caught in the act of turning on its associated G-protein.
--Different adrenergic subtypes may be triggered by the same drug, causing unwanted side effects. But in 2010 Kobilka showed that adrenergic receptors' outward facing portions contain sections that, while not themselves directly involved in binding to molecules from outside the cell, can influence how well one or another molecule fits into a beta-adrenergic receptor's binding pocket. These small sections vary widely from one adrenergic-receptor subtype to the next. Kobilka's discovery opens up a whole new path for developing whole new classes of drugs that can differentiate between the many different adrenergic-receptor subtypes, potentially reducing or eliminating side effects.
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