Structural Basis of Telomerase Inhibition by the Highly Specific BIBR1532

Christopher Bryan; Cory Rice; Hunter Hoffman; Michael Harkisheimer; Melanie Sweeney; Emmanuel Skordalakes

doi:10.1016/j.str.2015.08.006

Structural Basis of Telomerase Inhibition by the Highly Specific BIBR1532

Structure. 2015 Oct 6;23(10):1934-1942. doi: 10.1016/j.str.2015.08.006. Epub 2015 Sep 10.

Authors

Christopher Bryan¹, Cory Rice², Hunter Hoffman³, Michael Harkisheimer³, Melanie Sweeney¹, Emmanuel Skordalakes⁴

Affiliations

¹ The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA; Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, PA 19104, USA.
² The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA; Department of Biochemistry, University of Pennsylvania, Philadelphia, PA 19104, USA.
³ The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA.
⁴ The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA; Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, PA 19104, USA; Department of Biochemistry, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: skorda@wistar.org.

Abstract

BIBR1532 is a highly specific telomerase inhibitor, although the molecular basis for inhibition is unknown. Here we present the crystal structure of BIBR1532 bound to Tribolium castaneum catalytic subunit of telomerase (tcTERT). BIBR1532 binds to a conserved hydrophobic pocket (FVYL motif) on the outer surface of the thumb domain. The FVYL motif is near TRBD residues that bind the activation domain (CR4/5) of hTER. RNA binding assays show that the human TERT (hTERT) thumb domain binds the P6.1 stem loop of CR4/5 in vitro. hTERT mutations of the FVYL pocket alter wild-type CR4/5 binding and cause telomere attrition in cells. Furthermore, the hTERT FVYL mutations V1025F, N1028H, and V1090M are implicated in dyskeratosis congenita and aplastic anemia, further supporting the biological and clinical relevance of this novel motif. We propose that CR4/5 contacts with the telomerase thumb domain contribute to telomerase ribonucleoprotein assembly and promote enzymatic activity.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Amino Acid Motifs
Aminobenzoates / chemistry*
Aminobenzoates / pharmacology
Animals
Antineoplastic Agents / chemistry*
Antineoplastic Agents / pharmacology
Binding Sites
Catalytic Domain / genetics
Cell Line
Crystallography, X-Ray
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology
Escherichia coli / genetics
Escherichia coli / metabolism
Fibroblasts / cytology
Fibroblasts / drug effects
Fibroblasts / enzymology
Gene Expression
Humans
Insect Proteins / antagonists & inhibitors*
Insect Proteins / genetics
Insect Proteins / metabolism
Kinetics
Models, Molecular
Molecular Sequence Data
Mutation
Naphthalenes / chemistry*
Naphthalenes / pharmacology
Protein Binding
Protein Interaction Domains and Motifs
Protein Structure, Secondary
RNA / chemistry*
RNA / metabolism
Recombinant Proteins / chemistry
Recombinant Proteins / genetics
Recombinant Proteins / metabolism
Telomerase / antagonists & inhibitors*
Telomerase / genetics
Telomerase / metabolism
Tribolium

Substances

Aminobenzoates
Antineoplastic Agents
BIBR 1532
Enzyme Inhibitors
Insect Proteins
Naphthalenes
Recombinant Proteins
RNA
TERT protein, human
Telomerase

Associated data

PDB/5CQG

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding