8b6m
Tankyrase 2 in complex with an inhibitor
Structural highlights
FunctionTNKS2_HUMAN Poly-ADP-ribosyltransferase involved in various processes such as Wnt signaling pathway, telomere length and vesicle trafficking. Acts as an activator of the Wnt signaling pathway by mediating poly-ADP-ribosylation of AXIN1 and AXIN2, 2 key components of the beta-catenin destruction complex: poly-ADP-ribosylated target proteins are recognized by RNF146, which mediates their ubiquitination and subsequent degradation. Also mediates poly-ADP-ribosylation of BLZF1 and CASC3, followed by recruitment of RNF146 and subsequent ubiquitination. Mediates poly-ADP-ribosylation of TERF1, thereby contributing to the regulation of telomere length. May also regulate vesicle trafficking and modulate the subcellular distribution of SLC2A4/GLUT4-vesicles.[1] [2] [3] [4] Publication Abstract from PubMedDesigning inhibitors is a complex task that requires a deep understanding of protein-ligand interactions and their dynamics. Ligands often interact with multiple binding subsites, with noncovalent interactions affecting binding affinity. Conformational changes and plasticity of both, the ligand and the protein influence binding energetics. We investigated the tankyrase ADP-ribosyltransferase as a promising drug target regulating many cellular pathways. Despite the existence of diverse tankyrase inhibitors, their binding energetics and contributions of flexible cryptic subpockets to binding affinity remain elusive. To examine these aspects, we deconstructed inhibitors to key fragments, dissected their energetic contribution to the affinity, and determined their binding mode by X-ray crystallography. Varying ligand efficiencies of the deconstructed, pocket-binding fragments revealed the cryptic nature of subpockets. These insights enabled us to redesign inhibitors with novel linkers, the observed key area for optimization, increasing the potency in enzymatic and cell-based assays by 7.5-fold and 6.2-fold compared to the parent ligand. Deconstruction of Dual-Site Tankyrase Inhibitors Provides Insights into Binding Energetics and Suggests Critical Hotspots for Ligand Optimization.,Sowa ST, Kucukdisli M, Mostinski Y, Schaller DA, Vinagreiro CS, Cirillo D, Bosetti C, Brinch SA, van Laar K, Wegert A, Leenders RGG, Krauss S, Waaler J, Volkamer A, Lehtio L, Nazare M J Med Chem. 2025 Apr 10;68(7):7263-7279. doi: 10.1021/acs.jmedchem.4c02845. Epub , 2025 Mar 25. PMID:40134122[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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