Hernandez-Sanchez, Wilnelly and Huang, Wei and Plucinsky, Brian and Garcia-Vazquez, Nelson and Robinson, Nathaniel J. and Schiemann, William P. and Berdis, Anthony J. and Skordalakes, Emmanuel and Taylor, Derek J. and Smogorzewska, Agata (2019) A non-natural nucleotide uses a specific pocket to selectively inhibit telomerase activity. PLOS Biology, 17 (4). e3000204. ISSN 1545-7885
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Abstract
Telomerase, a unique reverse transcriptase that specifically extends the ends of linear chromosomes, is up-regulated in the vast majority of cancer cells. Here, we show that an indole nucleotide analog, 5-methylcarboxyl-indolyl-2′-deoxyriboside 5′-triphosphate (5-MeCITP), functions as an inhibitor of telomerase activity. The crystal structure of 5-MeCITP bound to the Tribolium castaneum telomerase reverse transcriptase reveals an atypical interaction, in which the nucleobase is flipped in the active site. In this orientation, the methoxy group of 5-MeCITP extends out of the canonical active site to interact with a telomerase-specific hydrophobic pocket formed by motifs 1 and 2 in the fingers domain and T-motif in the RNA-binding domain of the telomerase reverse transcriptase. In vitro data show that 5-MeCITP inhibits telomerase with a similar potency as the clinically administered nucleoside analog reverse transcriptase inhibitor azidothymidine (AZT). In addition, cell-based studies show that treatment with the cell-permeable nucleoside counterpart of 5-MeCITP leads to telomere shortening in telomerase-positive cancer cells, while resulting in significantly lower cytotoxic effects in telomerase-negative cell lines when compared with AZT treatment.
Item Type: | Article |
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Subjects: | ScienceOpen Library > Biological Science |
Depositing User: | Managing Editor |
Date Deposited: | 09 Jan 2023 07:14 |
Last Modified: | 12 Aug 2024 11:25 |
URI: | http://scholar.researcherseuropeans.com/id/eprint/155 |