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X-Ray Crystallography at the NSLS

Finding drugs that specifically inactivate a protein essential for a disease process involves two technologies. First, the three-dimensional (3-D) atomic level structure of the protein must be known. Then, computer programs find small drugs that bind to a specific site in the 3-D atomic level structure of the protein and inactivate the protein.

Crystals of the adenovirus protease


X-ray diffraction pattern of the adenovirus protease crystal

The major technique for determining these structures is x-ray crystallography. At the National Synchrotron Light Source (NSLS) at Brookhaven Lab ó where life scientists are the largest and fastest growing group of facility users ó biologists have used the NSLSís intense x-rays to perform x-ray crystallographic studies to determine the structures of myriad proteins, including those from organisms responsible for common colds, Lyme disease, and AIDS.

In fact, work done in part at the NSLS to solve the structure of a cell-membrane protein essential to the function of all nerve and muscle cells led to a 2003 Nobel Prize in Chemistry for Roderick MacKinnon, who is a Rockefeller University professor and frequent user of the NSLS.

The first step in determining a proteinís 3-D atomic structure is to make a crystal with many copies of the protein (see image, top right). The crystal is then mounted inside an experimental station at the end of a beam line of the NSLS x-ray ring.

When a beam of high-intensity x-rays passes through the crystal, it diffracts, or bends, as it interacts with the electrons in the atoms of the protein. These x-rays then hit a detector, which records the scattering pattern as a series of dots (see image, above). Analysis of the dot pattern results in the generation of an electron-density map that bears a resemblance to the proteinís 3-D shape (see image, bottom left).

Knowing the sequence of amino acids that make up the protein, scientists then fit that sequence into the electron-density framework to yield a 3-D map of every atom in the protein (see image, bottom right).


Electron-density map of the x-ray diffraction pattern


How the amino acids of the adenovirus protease fit into the electron-density map


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