Theoretical model of complex between phosphoglycerate kinase 1 and DJ1

Bilsland, A. , Boyd, S., Turnbull, A., Jenkinson, D., Roffey, J. and Keith, N. (2019) Theoretical model of complex between phosphoglycerate kinase 1 and DJ1. [Data Collection]

Datacite DOI: 10.5452/ma-4hhdq
Enlighten Publications URI: http://eprints.gla.ac.uk/id/eprint/191027

Collection description

Telomere signalling and metabolic dysfunction are hallmarks of cell aging, and are associated with a variety of pathologies. Identification of new agents targeting these processes might provide therapeutic opportunities, including chemoprevention strategies against cancer predisposition. Here we report identification and characterization of a pyrazolopyrimidine compound series that emerged from screens focused on cell immortality pathways and whose targets are glycolytic kinase PGK1 and oxidative stress sensor DJ1. We initially performed structure-activity studies on the series to develop an analogue suitable for use as a photoaffinity probe to deconvolute the cellular targets. Biophysical and structural analyses confirmed these targets, pointing to the possibility that PGK1/DJ1 interact, which we confirmed by immunoprecipitation. We additionally performed in silico structural modelling to identify a putative mechanism of complex formation. Glucose homeostasis and oxidative stress have previously been linked to telomere signalling and exemplar compound CRT0063465 was found to block hypoglycaemic telomere shortening. Intriguingly, we find that both PGK1 and DJ1 bind to TRF2 and telomeric DNA. Compound treatment not only modulates these interactions but also affects composition of the Shelterin complex, in addition to conferring cellular protection from cytotoxicity due to bleomycin and desferroxamine. These results highlight the power of chemical approaches in discovery of novel biological mechanisms and demonstrate therapeutic potential of the compound series.

College / School: College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Date Deposited: 15 Aug 2019 13:04
Funder's Name: Cancer Research UK (CRUK), Cancer Research UK (CRUK), Cancer Research UK (CRUK), Cancer Research UK (CRUK)
URI: http://researchdata.gla.ac.uk/id/eprint/860

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Bilsland, A. , Boyd, S., Turnbull, A., Jenkinson, D., Roffey, J. and Keith, N. (2019); Theoretical model of complex between phosphoglycerate kinase 1 and DJ1

ModelArchive, SIB Swiss Institute of Bioinformatics and Biozentrum, University of Basel

DOI: 10.5452/ma-4hhdq

Retrieved: 2020-10-21