6ETJ

HUMAN PFKFB3 IN COMPLEX WITH KAN0438241

6ETJ の概要

• エントリーDOI: 10.2210/pdb6etj/pdb
• 分子名称: 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3, DIMETHYL SULFOXIDE, 6-O-phosphono-beta-D-fructofuranose, ... (6 entities in total)
• 機能のキーワード: dna damage repair, homologous recombination, glycolysis, nucleotide metabolism, pfkfb3, antitumor protein
• 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: 60941.96

構造登録者

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. (登録日: 2017-10-26, 公開日: 2018-11-07, 最終更新日: 2025-04-09)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.51 Å)