6ETJ

HUMAN PFKFB3 IN COMPLEX WITH KAN0438241

Summary for 6ETJ

• Entry DOI: 10.2210/pdb6etj/pdb
• Descriptor: 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3, DIMETHYL SULFOXIDE, 6-O-phosphono-beta-D-fructofuranose, ... (6 entities in total)
• Functional Keywords: dna damage repair, homologous recombination, glycolysis, nucleotide metabolism, pfkfb3, antitumor protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 60941.96

Authors

Gustafsson, N.M.S.,Lundback, T.,Farnegardh, K.,Groth, P.,Wiitta, E.,Jonsson, M.,Hallberg, K.,Pennisi, R.,Huguet Ninou, A.,Martinsson, J.,Norstrom, C.,Schultz, J.,Andersson, M.,Markova, N.,Marttila, P.,Norin, M.,Olin, T.,Helleday, T. (deposition date: 2017-10-26, release date: 2018-11-07, Last modification date: 2025-04-09)

Primary citation

Gustafsson, N.M.S.,Farnegardh, K.,Bonagas, N.,Ninou, A.H.,Groth, P.,Wiita, E.,Jonsson, M.,Hallberg, K.,Lehto, J.,Pennisi, R.,Martinsson, J.,Norstrom, C.,Hollers, J.,Schultz, J.,Andersson, M.,Markova, N.,Marttila, P.,Kim, B.,Norin, M.,Olin, T.,Helleday, T.
Targeting PFKFB3 radiosensitizes cancer cells and suppresses homologous recombination.
Nat Commun, 9:3872-3872, 2018

PubMed Abstract: The glycolytic PFKFB3 enzyme is widely overexpressed in cancer cells and an emerging anti-cancer target. Here, we identify PFKFB3 as a critical factor in homologous recombination (HR) repair of DNA double-strand breaks. PFKFB3 rapidly relocates into ionizing radiation (IR)-induced nuclear foci in an MRN-ATM-γH2AX-MDC1-dependent manner and co-localizes with DNA damage and HR repair proteins. PFKFB3 relocalization is critical for recruitment of HR proteins, HR activity, and cell survival upon IR. We develop KAN0438757, a small molecule inhibitor that potently targets PFKFB3. Pharmacological PFKFB3 inhibition impairs recruitment of ribonucleotide reductase M2 and deoxynucleotide incorporation upon DNA repair, and reduces dNTP levels. Importantly, KAN0438757 induces radiosensitization in transformed cells while leaving non-transformed cells unaffected. In summary, we identify a key role for PFKFB3 enzymatic activity in HR repair and present KAN0438757, a selective PFKFB3 inhibitor that could potentially be used as a strategy for the treatment of cancer.

PubMed: 30250201
DOI: 10.1038/s41467-018-06287-x

Experimental method

X-RAY DIFFRACTION (2.51 Å)