8B6M

Tankyrase 2 in complex with an inhibitor

8B6M の概要

• エントリーDOI: 10.2210/pdb8b6m/pdb
• 分子名称: Poly [ADP-ribose] polymerase tankyrase-2, ~{N}-(2-methoxyphenyl)-4-[[2-(4-oxidanylidene-3~{H}-quinazolin-2-yl)ethyl-(thiophen-2-ylmethyl)carbamoyl]amino]benzamide, SULFATE ION, ... (7 entities in total)
• 機能のキーワード: inhibitor, transferase
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 51406.61

構造登録者

Bosetti, C.,Sowa, S.T.,Lehtio, L. (登録日: 2022-09-27, 公開日: 2023-10-11, 最終更新日: 2025-04-30)

主引用文献

Sowa, S.T.,Kucukdisli, M.,Mostinski, Y.,Schaller, D.A.,Vinagreiro, C.S.,Cirillo, D.,Bosetti, C.,Brinch, S.A.,van Laar, K.,Wegert, A.,Leenders, R.G.G.,Krauss, S.,Waaler, J.,Volkamer, A.,Lehtio, L.,Nazare, M.
Deconstruction of Dual-Site Tankyrase Inhibitors Provides Insights into Binding Energetics and Suggests Critical Hotspots for Ligand Optimization.
J.Med.Chem., 68:7263-7279, 2025

PubMed Abstract: Designing 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.

PubMed: 40134122
DOI: 10.1021/acs.jmedchem.4c02845

実験手法

X-RAY DIFFRACTION (1.6 Å)