5np8
From Proteopedia
PGK1 in complex with CRT0063465 (3-[2-(4-bromophenyl)-5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-6-yl]propanoic acid)
Structural highlights
DiseasePGK1_HUMAN Defects in PGK1 are the cause of phosphoglycerate kinase 1 deficiency (PGK1D) [MIM:300653. It is a condition with a highly variable clinical phenotype that includes hemolytic anemia, rhabdomyolysis, myopathy and neurologic involvement. Patients can express one or more of these manifestations.[1] [2] [3] [4] [5] [6] [7] [8] [9] FunctionPGK1_HUMAN In addition to its role as a glycolytic enzyme, it seems that PGK-1 acts as a polymerase alpha cofactor protein (primer recognition protein). Publication Abstract from PubMedTelomere 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. A Novel Pyrazolopyrimidine Ligand of Human PGK1 and Stress Sensor DJ1 Modulates the Shelterin Complex and Telomere Length Regulation.,Bilsland AE, Liu Y, Turnbull A, Sumpton D, Stevenson K, Cairney CJ, Boyd SM, Roffey J, Jenkinson D, Keith WN Neoplasia. 2019 Aug 8;21(9):893-907. doi: 10.1016/j.neo.2019.07.008. PMID:31401411[10] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
| ||||||||||||||||||||
Categories: Homo sapiens | Large Structures | Bilsland AE | Cairney CJ | Jenkinson D | Keith WN | Liu Y | Roffey J | Stevenson K | Sumpton D | Turnbull AP
