title: Structural basis and selectivity of tankyrase inhibition by a Wnt signaling inhibitor WIKI4.
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.
authors.affiliation: Biocenter Oulu, Department of Biochemistry, University of Oulu, Oulu, Finland.
authors.forename: Teemu
authors.initials: T
authors.lastname: Haikarainen
authors.forename: Harikanth
authors.initials: H
authors.lastname: Venkannagari
authors.forename: Mohit
authors.initials: M
authors.lastname: Narwal
authors.forename: Ezeogo
authors.initials: E
authors.lastname: Obaji
authors.forename: Hao-Wei
authors.initials: HW
authors.lastname: Lee
authors.forename: Yves
authors.initials: Y
authors.lastname: Nkizinkiko
authors.forename: Lari
authors.initials: L
authors.lastname: Lehtiö
mesh_terms: D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000737:chemistry*; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors; D006801:Humans; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D009243:NAD / Q000737:chemistry; D053644:Naphthalimides / Q000737:chemistry*; D011485:Protein Binding; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics; D012680:Sensitivity and Specificity; D038501:Tankyrases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D014230:Triazoles / Q000737:chemistry*; D060449:Wnt Signaling Pathway
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D053644:Naphthalimides; D011994:Recombinant Proteins; D014230:Triazoles; C581555:WIKI4 compound; D009243:NAD; C437334:TNKS2 protein, human; D038501:Tankyrases