6E53

Structure of TERT in complex with a novel telomerase inhibitor

Summary for 6E53

• Entry DOI: 10.2210/pdb6e53/pdb
• Descriptor: Telomerase reverse transcriptase, RNA/DNA hairpin, MAGNESIUM ION, ... (4 entities in total)
• Functional Keywords: telomerase, catalytic subunit, telomerase inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Tribolium castaneum (red flour beetle); More
• Total number of polymer chains: 2
• Total formula weight: 78333.05

Authors

Hernandez-Sanchez, W.,Huang, W.,Plucinsky, B.,Garcia-Vazquez, N.,Berdis, A.J.,Skordalakes, E.,Taylor, D.J. (deposition date: 2018-07-19, release date: 2019-03-27, Last modification date: 2023-10-11)

Primary citation

Hernandez-Sanchez, W.,Huang, W.,Plucinsky, B.,Garcia-Vazquez, N.,Robinson, N.J.,Schiemann, W.P.,Berdis, A.J.,Skordalakes, E.,Taylor, D.J.
A non-natural nucleotide uses a specific pocket to selectively inhibit telomerase activity.
Plos Biol., 17:e3000204-e3000204, 2019

PubMed 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.

PubMed: 30951520
DOI: 10.1371/journal.pbio.3000204

Experimental method

X-RAY DIFFRACTION (2.8 Å)