Structural basis of selective inhibition of human tankyrases

Mohit Narwal, Harikanth Venkannagari, Lari Lehtiö

Research output: Contribution to journalArticle

88 Citations (Scopus)

Abstract

Tankyrases are poly(ADP-ribose) polymerases that have many cellular functions. They play pharmaceutically important roles, at least in telomere homeostasis and Wnt signaling, by covalently ADP-ribosylating target proteins and consequently regulating their functions. These features make tankyrases potential targets for treatment of cancer. We report here crystal structures of human tankyrase 2 catalytic fragment in complex with a byproduct, nicotinamide, and with selective inhibitors of tankyrases (IWR-1) and PARPs 1 and 2 (olaparib). Binding of these inhibitors to tankyrase 2 induces specific conformational changes. The crystal structures explain the selectivity of the inhibitors, reveal the flexibility of a substrate binding loop, and explain existing structure-activity relationship data. The first crystal structure of a PARP enzyme in complex with a potent inhibitor, IWR-1, that does not bind to the widely utilized nicotinamide-binding site makes the structure valuable for development of PARP inhibitors in general.

Original languageEnglish (US)
Pages (from-to)1360-1367
Number of pages8
JournalJournal of Medicinal Chemistry
Volume55
Issue number3
DOIs
StatePublished - Feb 9 2012
Externally publishedYes

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Tankyrases
Niacinamide
Telomere Homeostasis
Poly(ADP-ribose) Polymerases
Structure-Activity Relationship
Adenosine Diphosphate
Binding Sites
human TNKS protein
Enzymes
Neoplasms
Proteins

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Structural basis of selective inhibition of human tankyrases. / Narwal, Mohit; Venkannagari, Harikanth; Lehtiö, Lari.

In: Journal of Medicinal Chemistry, Vol. 55, No. 3, 09.02.2012, p. 1360-1367.

Research output: Contribution to journalArticle

Narwal, Mohit ; Venkannagari, Harikanth ; Lehtiö, Lari. / Structural basis of selective inhibition of human tankyrases. In: Journal of Medicinal Chemistry. 2012 ; Vol. 55, No. 3. pp. 1360-1367.
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