The ribonucleoprotein enzyme telomerase maintains telomeres in most cancers and is essentially undetectable in somatic cells, creating the possibility that telomerase inhibition could selectively repress cancer cell growth with minimal side effects. The three primary components of the human telomerase ribonucleoprotein enzyme are the catalytic subunit (telomerase reverse transcriptase, hTERT), an RNA component containing the template (hTR), and the protein dyskerin (DKC). The large catalytic subunit (hTERT) contains four conserved structural domains: the telomerase essential N terminus (TEN), the telomerase RNA binding domain (TRBD), the reverse transcriptase (RT) domain and the C-terminal extension (CTE). Crystal structures of human telomerase components have proved elusive due to difficulties in obtaining purified protein in sufficient quantities.
Because of this, we have created highly predictive homology models of human telomerase components. These models have explained our biochemical data at a molecular level, leading to a greater understanding of telomerase function (1, 2). Using molecular dynamics simulations, we have modelled the interactions between hTERT and DNA, providing a molecular basis for a disease-associated telomerase mutation, and the first direct evidence for a role of the C-terminal extension in DNA binding affinity (3). Finally, these models have been docked into single particle electron microscopy envelopes, allowing us to visualise the location and structural interplay between the hTERT structural domains for the first time.