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Finally, the researchers were able to obtain an extremely detailed three-dimensional map, elucidating the position of each individual atom within the TEN domain. Their studies revealed that TEN was characterized by a deep groove on its surface. "But," Cech said, "a protein crystal structure without its relevant partners is not very informative." So the team went on to do further analysis.

Telomerase has to grab on to the end of a chromosome in order to extend it, and Cech said scientists had previously decided that the region of the protein his lab was now studying might contain the essential "anchor site." Indeed, the TEN domain was able to grip telomeric DNA in a test tube, and when the researchers made a series of single amino acids changes within the domain, they found that three of these severely affected the binding of the chromosome end. "They turned out to be lined up right within that groove," Cech said.

The scientists found that these same mutations abolished telomerase's ability to extend telomeres, demonstrating that the groove was important for active telomerase.

"We now have a detailed picture of the part of telomerase that forms this anchor site, and in fact have identified a groove within the protein that is what is really holding on to the end of the chromosome," Cech said. The very tip of the chromosome must remain free to allow access to the site on the enzyme that directly extends the telomeres, Cech pointed out, so the anchor site secures the DNA molecule nearby, slightly closer to its center.

Cech is optimistic that the new portrait of the TEN domain will speed the development of telomerase inhibitors as chemotherapeutic agents. "A molecule that would sit in that groove ?even though it's far away from the active site ?looks like it would completely abolish the ability of telomerase to work." This expands the possibilities for drug design, he said. "Instead o
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Source:Howard Hughes Medical Institute