title: Novel binding mode of a potent and selective tankyrase inhibitor.
abstract: Tankyrases (TNKS1 and TNKS2) are key regulators of cellular processes such as telomere pathway and Wnt signaling. IWRs (inhibitors of Wnt response) have recently been identified as potent and selective inhibitors of tankyrases. However, it is not clear how these IWRs interact with tankyrases. Here we report the crystal structure of the catalytic domain of human TNKS1 in complex with IWR2, which reveals a novel binding site for tankyrase inhibitors. The TNKS1/IWR2 complex provides a molecular basis for their strong and specific interactions and suggests clues for further development of tankyrase inhibitors.
authors.affiliation: Department of Molecular Structure, Amgen, Cambridge, Massachusetts, United States of America.
authors.forename: Hakan
authors.initials: H
authors.lastname: Gunaydin
authors.forename: Yan
authors.initials: Y
authors.lastname: Gu
authors.forename: Xin
authors.initials: X
authors.lastname: Huang
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D038501:Tankyrases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics; D060449:Wnt Signaling Pathway / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D038501:Tankyrases; C437334:TNKS2 protein, human; C418109:TNKS protein, human