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Structural basis and selectivity of tankyrase inhibition by a Wnt signaling inhibitor WIKI4.

Haikarainen T, Venkannagari H, Narwal M, Obaji E, Lee HW, Nkizinkiko Y, Lehtiö L - PLoS ONE (2013)

Bottom Line: Here we confirm that WIKI4 is a high potency tankyrase inhibitor and that it selectively inhibits tankyrases over other ARTD enzymes tested.The structure revealed a novel binding mode to the adenosine subsite of the donor NAD(+) binding groove of the catalytic domain.Our results form a structural basis for further development of potent and selective tankyrase inhibitors based on the WIKI4 scaffold.

View Article: PubMed Central - PubMed

Affiliation: Biocenter Oulu, Department of Biochemistry, University of Oulu, Oulu, Finland.

ABSTRACT
Recently a novel inhibitor of Wnt signaling was discovered. The compound, WIKI4, was found to act through tankyrase inhibition and regulate β-catenin levels in many cancer cell lines and human embryonic stem cells. Here we confirm that WIKI4 is a high potency tankyrase inhibitor and that it selectively inhibits tankyrases over other ARTD enzymes tested. The binding mode of the compound to tankyrase 2 was determined by protein X-ray crystallography to 2.4 Å resolution. The structure revealed a novel binding mode to the adenosine subsite of the donor NAD(+) binding groove of the catalytic domain. Our results form a structural basis for further development of potent and selective tankyrase inhibitors based on the WIKI4 scaffold.

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Interactions of WIKI4 with TNKS2 catalytic domain.a) Chemical structure of WIKI4. b) Binding mode of WIKI4 to monomer A. c) Binding mode of WIKI4 to monomer B.
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pone-0065404-g005: Interactions of WIKI4 with TNKS2 catalytic domain.a) Chemical structure of WIKI4. b) Binding mode of WIKI4 to monomer A. c) Binding mode of WIKI4 to monomer B.

Mentions: Although WIKI4 does not interact with the nicotinamide site, the pyridine ring of the compound (Figure 5a) is located near the site in a hydrophobic pocket lined by Tyr1060, Tyr1071, Ile1075, Ile1051, and Gly1053 (Figure 5b,c). Nevertheless, it does not form an efficient π-π stacking interaction with Tyr1071 like most other ARTD inhibitors, but it is stacking with Tyr1060 (Figure 5b,c). The amide of the pyridine points outside of the pocket towards the nicotinamide site and is situated in a more polar environment near (3.9 Å) the hydroxyl of Tyr1071 (Figure 5b,c).


Structural basis and selectivity of tankyrase inhibition by a Wnt signaling inhibitor WIKI4.

Haikarainen T, Venkannagari H, Narwal M, Obaji E, Lee HW, Nkizinkiko Y, Lehtiö L - PLoS ONE (2013)

Interactions of WIKI4 with TNKS2 catalytic domain.a) Chemical structure of WIKI4. b) Binding mode of WIKI4 to monomer A. c) Binding mode of WIKI4 to monomer B.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3675114&req=5

pone-0065404-g005: Interactions of WIKI4 with TNKS2 catalytic domain.a) Chemical structure of WIKI4. b) Binding mode of WIKI4 to monomer A. c) Binding mode of WIKI4 to monomer B.
Mentions: Although WIKI4 does not interact with the nicotinamide site, the pyridine ring of the compound (Figure 5a) is located near the site in a hydrophobic pocket lined by Tyr1060, Tyr1071, Ile1075, Ile1051, and Gly1053 (Figure 5b,c). Nevertheless, it does not form an efficient π-π stacking interaction with Tyr1071 like most other ARTD inhibitors, but it is stacking with Tyr1060 (Figure 5b,c). The amide of the pyridine points outside of the pocket towards the nicotinamide site and is situated in a more polar environment near (3.9 Å) the hydroxyl of Tyr1071 (Figure 5b,c).

Bottom Line: Here we confirm that WIKI4 is a high potency tankyrase inhibitor and that it selectively inhibits tankyrases over other ARTD enzymes tested.The structure revealed a novel binding mode to the adenosine subsite of the donor NAD(+) binding groove of the catalytic domain.Our results form a structural basis for further development of potent and selective tankyrase inhibitors based on the WIKI4 scaffold.

View Article: PubMed Central - PubMed

Affiliation: Biocenter Oulu, Department of Biochemistry, University of Oulu, Oulu, Finland.

ABSTRACT
Recently a novel inhibitor of Wnt signaling was discovered. The compound, WIKI4, was found to act through tankyrase inhibition and regulate β-catenin levels in many cancer cell lines and human embryonic stem cells. Here we confirm that WIKI4 is a high potency tankyrase inhibitor and that it selectively inhibits tankyrases over other ARTD enzymes tested. The binding mode of the compound to tankyrase 2 was determined by protein X-ray crystallography to 2.4 Å resolution. The structure revealed a novel binding mode to the adenosine subsite of the donor NAD(+) binding groove of the catalytic domain. Our results form a structural basis for further development of potent and selective tankyrase inhibitors based on the WIKI4 scaffold.

Show MeSH
Related in: MedlinePlus