Designing drugs that can better target telomerase, though, has been limited by lack of understanding of the enzyme’s molecular structure.
Now, however, researchers at the University of California, Berkeley used cryo-electron microscopy (Cryo-EM) to achieve significantly more detailed images of human telomerase.
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“The best previous images of human telomerase had a resolution of only 30 Ångstroms; we were able to get about 7 to 8 Ångstroms resolution,” Thi Hoang Duong Nguyen, a postdoctoral fellow at the University of California, Berkeley and lead author of the newly published description, said in a news release accompanying the paper’s publication.4
The improved resolution revealed the protein subunits of the enzyme and, coupled with computer-assisted modeling, produced three-dimensional architectural visualizations.
The images, Nguyen and her co-authors wrote, showed “two flexibly RNA-tethered lobes: the catalytic core with telomerase reverse transcriptase (TERT) and conserved motifs of telomerase RNA (hTR), and an H/ACA ribonucleoprotein (RNP).”
The result, they concluded, “opens new opportunities for the design and screening of inhibitors targeting hTR folding and TERT interaction that will hold promise as general anti-cancer therapeutic agents.”
References
- Buseman CM, Wright WE, Shay JW. Is telomerase a viable target in cancer? Mutation Research. 2012;730(1-2):90-97. doi:10.1016/j.mrfmmm.2011.07.006.
- Jafri MA, Ansari SA, Alqahtani MH, and Shay JW. Roles of telomeres and telomerase in cancer, and advances in telomerase-targeted therapies. Genome Medicine 20168:69. 20 June 2016. https://doi.org/10.1186/s13073-016-0324-x
- Marian CO, Cho SK, McEllin BM, et al. The Telomerase Antagonist Imetelstat Efficiently Targets Glioblastoma Tumor-Initiating Cells Leading to Decreased Proliferation and Tumor Growth. Clinical cancer research : an official journal of the American Association for Cancer Research. 2010;16(1):154-163. doi:10.1158/1078-0432.CCR-09-2850
- Nguyen THD, Tam J, Wu RA, Greber BJ, Toso D, Nogales E, and Collins K. Cryo-EM structure of substrate-bound human telomerase holoenzyme. Nature volume 557, pages190–195 (2018). 25 April 2018. doi.org/10.1038/s41586-018-0062-x
