Leiden researchers elucidate protein structure at highest resolution ever
Never before has the crystal structure of a human protein molecule in a cell wall been so crystal clear. Leiden researchers Ad IJzerman and Laura Heitman in collaboration with their American colleagues created the most detailed crystal structure of a target protein ever made for medicinal purposes. The researchers published their results in Science
The protein in question is the adenosine A2A-receptor, the most important receptor for caffeine in the body. It is associated with Parkinson’s disease. The class of approximately 800 proteins to which the adenosine A2A-receptor belongs forms the basis for approximately half of all medicinal drugs. ‘No wonder that researchers throughout the entire world have been busy for decades trying to figure out what they look like,’ says IJzerman.
In order to find out whether drugs work you need to know how the receptors in the cell wall are organised. An important way of doing this is to crystallise the protein, so that it can be looked at using X-rays. In 2008, IJzerman and his research team managed to determine the crystal structure of the adenosine A2A receptor, but at a lower resolution. IJzerman: ‘Since then a handful of structures of other receptors have appeared in the literature, but at such a low resolution that in some cases it is hard to determine how drugs are supposed to bind to such a receptor.’ Heitman adds: ‘With our new structure we have created images of a protein in the human cell wall at the highest resolution ever.’
The degree of detail of the new high-resolution crystal structure makes it possible to see things that were previously invisible. ‘It's like comparing what Galileo saw with his telescope to the images the Hubble telescope makes,’ says Ijzerman. For instance, it is now possible to see how water molecules play an important role in activating the adenosine A2A receptor. A water channel in the inactive receptor turns out to be disturbed in the process. The teams also discovered a hidden spot containing a sodium ion, outside the drug-binding cavity of the receptor. This gives insight into the way in which sodium ions influence the activity of hormones and neurotransmitters in the human body, something that has so far remained a mystery.
The high resolution structure was the result of a clever strategy by collaborators at the Scripps Institute in La Jolla (California). By connecting the receptor protein, which is fatty and therefore hard to crystallise, to another protein which can be crystallised easily, the researchers managed to produce minuscule crystals. The lysozyme protein had previously been used for this process, but this time they used proteins that crystallise even more easily and that fit the receptor better. In the end this yielded the high resolution structure which is so much more telling than any receptor structure previously made.
Research has shown that coffee drinkers tend to develop Parkinson’s disease less frequently. Caffeine blocks the adenosine A2A receptor, which is associated with this condition. The receptor also plays a crucial role in infections.
Liu W, Chun E, Thompson AA, Chubukov P, Xu F, Katritch V, Han GW, Roth CB, Heitman LH, IJzerman AP, Cherezov V, Stevens RC.
Structural Basis for Allosteric Regulation of GPCRs by Sodium Ions
Published in Science on 13 July 2012.
News article: Coffee and Parkinson's disease (October 2008)
Health, Life and Biosciences is one of the six themes for research at Leiden University.
(12 July 2012)