5NP8

PGK1 in complex with CRT0063465 (3-[2-(4-bromophenyl)-5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-6-yl]propanoic acid)

5NP8 の概要

• エントリーDOI: 10.2210/pdb5np8/pdb
• 分子名称: Phosphoglycerate kinase 1, 3-[2-(4-bromophenyl)-5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-6-yl]propanoic acid, 1,2-ETHANEDIOL, ... (5 entities in total)
• 機能のキーワード: kinase, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 45701.39

構造登録者

Turnbull, A.P.,Bilsland, A.E.,Liu, Y.,Sumpton, D.,Stevenson, K.,Cairney, C.J.,Roffey, J.,Jenkinson, D.,Keith, W.N. (登録日: 2017-04-13, 公開日: 2018-05-16, 最終更新日: 2024-01-17)

主引用文献

Bilsland, A.E.,Liu, Y.,Turnbull, A.,Sumpton, D.,Stevenson, K.,Cairney, C.J.,Boyd, S.M.,Roffey, J.,Jenkinson, D.,Keith, W.N.
A Novel Pyrazolopyrimidine Ligand of Human PGK1 and Stress Sensor DJ1 Modulates the Shelterin Complex and Telomere Length Regulation.
Neoplasia, 21:893-907, 2019

PubMed Abstract: Telomere signaling and metabolic dysfunction are hallmarks of cell aging. New agents targeting these processes might provide therapeutic opportunities, including chemoprevention strategies against cancer predisposition. We report identification and characterization of a pyrazolopyrimidine compound series identified from screens focused on cell immortality and whose targets are glycolytic kinase PGK1 and oxidative stress sensor DJ1. We performed structure-activity studies on the series to develop a photoaffinity probe to deconvolute the cellular targets. In vitro binding and structural analyses confirmed these targets, suggesting that PGK1/DJ1 interact, which we confirmed by immunoprecipitation. Glucose homeostasis and oxidative stress are linked to telomere signaling and exemplar compound CRT0063465 blocked hypoglycemic telomere shortening. Intriguingly, PGK1 and DJ1 bind to TRF2 and telomeric DNA. Compound treatment modulates these interactions and also affects Shelterin complex composition, while conferring cellular protection from cytotoxicity due to bleomycin and desferroxamine. These results demonstrate therapeutic potential of the compound series.

PubMed: 31401411
DOI: 10.1016/j.neo.2019.07.008

実験手法

X-RAY DIFFRACTION (1.9 Å)