In a study reported in Neuron, the scientists created a 3-D computer model of one type of glutamate receptor that can serve as a template for all others. The model revealed that glutamate receptors have two hemispherical lobes facing each other and held together by a hinge of amino acids. It also showed that these receptors share the characteristic behavior of both Pacman and the Venus flytrap: they sit on cell membranes with their "mouths" wide open and shut their "jaws" to nab passing glutamate molecules. This nabbing leads to the opening of sodium and potassium channels in the cell, which triggers a chain of molecular processes, some of which are involved in memory.
Three-D protein models are extremely important because they not only help clarify the proteins' properties but can also be used in the computerized search for new molecules with therapeutic potential.
"Our model may become a valuable tool for developing drugs for a variety of glutamate-related disorders, including stroke, head trauma, epilepsy and perhaps also for failing memory in Alzheimer disease," says team leader Prof. Vivian Teichberg of Weizmann's Neurobiology Department.
Teichberg's team turned to computers because glutamate receptors do not crystallize and therefore cannot be studied by X-ray crystallography, the usual method of determining 3-D protein structures. The receptor model was built using a set of computer programs that combined information about the protein's amino acids with the known structure of two bacterial proteins believed to be evolutionary predecessors of glutamate receptors.
The scientists then conducted various lab experiments confirming that the model accurately represents the actual receptor. Computerized drug development, in which the new model may be used, works on the "Cinderella's shoe" principle: the computer program tries to match the receptor's "shoe," or binding site, with the "foot," 3-D models of numerous potentially useful molecules, until it finds one that fits, and the molecule is then tested in the lab.
The model created by Teichberg's team may, for example, help develop new synthetic molecules that would compete with glutamate, blocking its receptors and thereby limiting its activity in cases such as stroke and head trauma, where excessive glutamate is known to cause damage by killing brain cells.
Prof. Teichberg, who holds the Louis and Florence Katz-Cohen Chair of Neuropharmacology, worked with doctoral students Yoav Paas and Itzhak Mano of the Weizmann Institute's Neurobiology Department, Dr. Miriam Eisenstein, head of the Molecular Modeling Unit in the Weizmann Institute's Chemical Services, and Prof. Anne Devillers-Thiery and laboratory assistant Francois Medevielle of the Pasteur Institute. The study was supported by the Minerva Foundation, Munich, Germany, the Golden Charitable Trust, and the Weizmann Institute's Leo and Julia Forchheimer Center for Molecular Genetics and the Kimmelman Center for Biomolecular Assembly.
The Weizmann Institute of Science is a major center of scientific research and graduate study located in Rehovot, Israel.