A non-natural nucleotide uses a specific pocket to selectively inhibit telomerase activity.
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 i...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2019-04-01
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| Series: | PLoS Biology |
| Online Access: | https://doi.org/10.1371/journal.pbio.3000204 |
| _version_ | 1819124315249967104 |
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| author | Wilnelly Hernandez-Sanchez Wei Huang Brian Plucinsky Nelson Garcia-Vazquez Nathaniel J Robinson William P Schiemann Anthony J Berdis Emmanuel Skordalakes Derek J Taylor |
| author_facet | Wilnelly Hernandez-Sanchez Wei Huang Brian Plucinsky Nelson Garcia-Vazquez Nathaniel J Robinson William P Schiemann Anthony J Berdis Emmanuel Skordalakes Derek J Taylor |
| author_sort | Wilnelly Hernandez-Sanchez |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-22T07:22:17Z |
| format | Article |
| id | doaj.art-89d34eb64c654bd6875333e2810f44f3 |
| institution | Directory Open Access Journal |
| issn | 1544-9173 1545-7885 |
| language | English |
| last_indexed | 2024-12-22T07:22:17Z |
| publishDate | 2019-04-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Biology |
| spelling | doaj.art-89d34eb64c654bd6875333e2810f44f32022-12-21T18:34:13ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852019-04-01174e300020410.1371/journal.pbio.3000204A non-natural nucleotide uses a specific pocket to selectively inhibit telomerase activity.Wilnelly Hernandez-SanchezWei HuangBrian PlucinskyNelson Garcia-VazquezNathaniel J RobinsonWilliam P SchiemannAnthony J BerdisEmmanuel SkordalakesDerek J TaylorTelomerase, 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.https://doi.org/10.1371/journal.pbio.3000204 |
| spellingShingle | Wilnelly Hernandez-Sanchez Wei Huang Brian Plucinsky Nelson Garcia-Vazquez Nathaniel J Robinson William P Schiemann Anthony J Berdis Emmanuel Skordalakes Derek J Taylor A non-natural nucleotide uses a specific pocket to selectively inhibit telomerase activity. PLoS Biology |
| title | A non-natural nucleotide uses a specific pocket to selectively inhibit telomerase activity. |
| title_full | A non-natural nucleotide uses a specific pocket to selectively inhibit telomerase activity. |
| title_fullStr | A non-natural nucleotide uses a specific pocket to selectively inhibit telomerase activity. |
| title_full_unstemmed | A non-natural nucleotide uses a specific pocket to selectively inhibit telomerase activity. |
| title_short | A non-natural nucleotide uses a specific pocket to selectively inhibit telomerase activity. |
| title_sort | non natural nucleotide uses a specific pocket to selectively inhibit telomerase activity |
| url | https://doi.org/10.1371/journal.pbio.3000204 |
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