Exploring the mechanism of inhibition of human telomerase by cysteine-reactive compounds

FEBS Lett. 2017 Mar;591(6):863-874. doi: 10.1002/1873-3468.12589. Epub 2017 Mar 1.


Telomerase is an almost universal cancer target that consists minimally of a core protein human telomerase reverse transcriptase (hTERT) and a RNA component human telomerase RNA (hTR). Some inhibitors of this enzyme are thought to function by the covalent binding to one or several cysteine residues; however, this inhibition mechanism has never been investigated because of the difficulty in producing telomerase. In this study, we use a recent method to produce recombinant hTERT to analyze the effect of cysteine-reactive inhibitors on telomerase. Using mass spectrometry and mutagenesis analysis, we identify several targeted residues in separated domains of the hTERT protein and show that cysteine-reactive reagents abolish the interaction with the CR4/5 region of hTR.

Keywords: cysteine; inhibitor; telomerase.

MeSH terms

  • Amino Acid Sequence
  • Binding Sites / genetics
  • Cysteine / chemistry
  • Cysteine / genetics
  • Cysteine / metabolism*
  • Humans
  • Mass Spectrometry / methods
  • Models, Molecular
  • Molecular Structure
  • Mutagenesis
  • Protein Binding
  • Protein Domains
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / metabolism*
  • Reverse Transcriptase Inhibitors / chemistry
  • Reverse Transcriptase Inhibitors / metabolism*
  • Reverse Transcriptase Inhibitors / pharmacology
  • Sequence Homology, Amino Acid
  • Structure-Activity Relationship
  • Telomerase / antagonists & inhibitors
  • Telomerase / genetics
  • Telomerase / metabolism*


  • Recombinant Proteins
  • Reverse Transcriptase Inhibitors
  • TERT protein, human
  • Telomerase
  • Cysteine