structure of enzyme essential in uncontrolled cancer growth AND AGING elucidated!

[Lani]

Telomerase Enzyme Structure Provides Significant New Target for Anti-Cancer Therapies [The Wistar Institute]
Philadelphia - November 13, 2007) - Inappropriate activation of a single enzyme, telomerase, is associated with the uncontrollable proliferation of cells seen in as many as 90 percent of all of human cancers. Since the mid-1990s, when telomerase was first identified in human tumors, scientists have eyed the enzyme as an ideal target for developing broadly effective anti-cancer drugs.
Now, researchers working at The Wistar Institute have brought this goal closer by deciphering the three-dimensional structure of a domain, or region, of the telomerase molecule essential for the activity of the enzyme. The findings, published November 13 in the journal Structure, may help scientists develop strategies to design the first direct inhibitors of telomerase.
Telomerase also has been shown to play a central role in normal aging, and the new study may shed light on that vital life process as well. The potential for creating new cancer treatments, however, is the most important immediate implication of the study.
"Knowing the physical structure of this complex will give pharmaceutical companies a direct target for designing drugs that disrupt a mechanism that telomerase uses to assemble itself," says Emmanuel Skordalakes, Ph.D., an assistant professor in the Gene Expression and Regulation Program at Wistar and senior author on the study. "Such drugs could well have significant anti-cancer activity."
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ABSTRACT: Structure of the RNA-Binding Domain of Telomerase: Implications for RNA Recognition and Binding [Structure]
Telomerase, a ribonucleoprotein complex, replicates the linear ends of eukaryotic chromosomes, thus taking care of the "end of replication problem." TERT contains an essential and universally conserved domain (TRBD) that makes extensive contacts with the RNA (TER) component of the holoenzyme, and this interaction is thought to facilitate TERT/TER assembly and repeat-addition processivity. Here, we present a high-resolution structure of TRBD from Tetrahymena thermophila. The nearly all-helical structure comprises a nucleic acid-binding fold suitable for TER binding. An extended pocket on the surface of the protein, formed by two conserved motifs (CP and T motifs) comprises TRBD's RNA-binding pocket. The width and the chemical nature of this pocket suggest that it binds both single- and double-stranded RNA, possibly stem I, and the template boundary element (TBE). Moreover, the structure provides clues into the role of this domain in TERT/TER stabilization and telomerase repeat-addition processivity