The 2012 Nobel Prize for Chemistry has been awarded to Robert J Lefkowitz and Brian K Kobilka for their work on G-Protein Coupled Receptors.
We say that there are five senses – sight, hearing, touch, taste and smell – but the cells in our bodies can also sense and react to a whole variety of chemicals called hormones and neurotransmitters. The work of Bob Lefkowitz and Brian Kobilka has shown that the way this happens in cells is similar for all the different types of sense.
The most important part of the process is a group of compounds called G-Protein Coupled Receptors (GPCRs). Nearly a thousand of these molecules are now known but they have many similarities. They are themselves proteins – long chains of amino acids wrapped up in a special shape. GPCRs are found in the membranes of cells. Their Loch Ness monster-like chains criss-cross the membrane seven times. The head of the molecule sticks out of the membrane and the tail pokes into the cell.
When a particular molecule, such as a hormone or an odour chemical, hits the exposed receptor end of a matching GPCR it bonds with it. This causes a change in the GPCR molecule that alters the shape of the end inside the cell. This causes a molecule called a G-protein to react with the end of GPCR and sets off a chain of reactions in the cell. In this way the cell responds to the molecules outside it. The GPCRs in the membrane of every cell each respond to a small number of molecules which are known as agonists.
Bob Lefkowitz was born in 1943 in New York. He studied medicine at Columbia University and at first was interested in cardiology (the study of the heart) because his father suffered and died from heart attacks. A year in a laboratory persuaded him to investigate how heart cells reacted to the hormone, adrenaline. In 1972 he was offered a post at Duke University in North Carolina, USA where he set up a laboratory to carry out his research. Lefkowitz and his team used agonist molecules containing a radioactive atom to follow what happened when they activated the receptors in heart cells. Over the next few years they worked out the role of the GPCRs.
Brian Kobilka was born in Little Falls, Minnesota in 1955. He took a degree in Biology and Chemistry before studying medicine at Yale University. In the 1980s Kobilka joined Lefkowitz’s team at Duke University. He was responsible for working out the DNA sequence for the gene that codes for the GPCR that is the receptor for adrenaline in heart cells. It was this work that lead to the discovery that all the GPCRs were similar. For example, Rhodopsin, the protein in retina cells that makes cells respond to light is a GPCR. They found GPCRs involved in the other senses and in the reaction of cells to other hormones and neurotransmitters. Later Kobilka moved to Stanford University, California to set up his own team of researchers. They have used X-ray crystallography to work out the shape of GPCR molecules and to observe them change when agonists bind with them.
As well as discovering how our cells respond to all sorts of different molecules, the work of Lefkowitz and Kobilka has resulted in the development of many medicinal drugs. There are molecules similar to agonists called antagonists or blockers. Antagonists stick to the end of the GPCR but do not make it change shape. Nothing happens inside the cell so the response is blocked. This work was used to design the beta-blocker drugs given to people with heart disease and the anti-histamines taken by hay-fever and allergy sufferers who have a strong reaction to certain molecules. Over half the drugs developed in the last forty years are molecules that interfere with the reaction of one GPCR or another.
Bob Lefkowitz and Brian Kobilka may describe themselves as cell biologists. The fact that they have been awarded the Nobel Prize for Chemistry shows the importance of chemistry in the processes that happen in cells. Using chemical techniques they have investigated the structure and properties of a particular group of molecules, the G-Protein Coupled Receptors. They have discovered how cells sense the world around them.
1 How many senses are there? Traditionally we say five but some scientists say there are many more. Make a list of all the things that you can sense e.g. sight is at least three different senses – dark and light, colour, movement.
2 Sketch a diagram of a GPCR molecule in the cell membrane from the description given in the article.
3 (A level) GPCR molecules are typical proteins made up of a polypeptide chain. Draw the structure of the peptide link between amino acids in a protein.
4 (A level) Each GPCR only binds with particular agonist molecules rather like an enzyme combines with reactants. Describe how the GPCR recognises and binds with particular agonists.
5 The Nobel Prize recognises discoveries that are exceptionally important. Evaluate the importance of Bob Lefkowitz’s and Brian Kobilka’s research.
6 Discover how Bob Lefkowitz’s childhood influenced his career.
You can find out more about the Nobel Prize for Chemistry at http://www.nobelprize.org/nobel_prizes/chemistry/laureates/2012/