4G1N

PKM2 in complex with an activator

4G1N の概要

• エントリーDOI: 10.2210/pdb4g1n/pdb
• 分子名称: Pyruvate kinase isozymes M1/M2, OXALATE ION, MAGNESIUM ION, ... (5 entities in total)
• 機能のキーワード: pyruvate kinase, aerobic glycolysis, activator, cancer metabolism, phosphorylation of pyruvate, transferase-activator complex, transferase/activator
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: P14618
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 228027.52

構造登録者

Kung, C.,Hixon, J.,Dang, L.,DeLaBarre, B.,Qian, K.C. (登録日: 2012-07-10, 公開日: 2012-10-10, 最終更新日: 2024-02-28)

主引用文献

Kung, C.,Hixon, J.,Choe, S.,Marks, K.,Gross, S.,Murphy, E.,Delabarre, B.,Cianchetta, G.,Sethumadhavan, S.,Wang, X.,Yan, S.,Gao, Y.,Fang, C.,Wei, W.,Jiang, F.,Wang, S.,Qian, K.,Saunders, J.,Driggers, E.,Woo, H.K.,Kunii, K.,Murray, S.,Yang, H.,Yen, K.,Liu, W.,Cantley, L.C.,Vander Heiden, M.G.,Su, S.M.,Jin, S.,Salituro, F.G.,Dang, L.
Small Molecule Activation of PKM2 in Cancer Cells Induces Serine Auxotrophy.
Chem.Biol., 19:1187-1198, 2012

PubMed Abstract: Proliferating tumor cells use aerobic glycolysis to support their high metabolic demands. Paradoxically, increased glycolysis is often accompanied by expression of the lower activity PKM2 isoform, effectively constraining lower glycolysis. Here, we report the discovery of PKM2 activators with a unique allosteric binding mode. Characterization of how these compounds impact cancer cells revealed an unanticipated link between glucose and amino acid metabolism. PKM2 activation resulted in a metabolic rewiring of cancer cells manifested by a profound dependency on the nonessential amino acid serine for continued cell proliferation. Induction of serine auxotrophy by PKM2 activation was accompanied by reduced carbon flow into the serine biosynthetic pathway and increased expression of high affinity serine transporters. These data support the hypothesis that PKM2 expression confers metabolic flexibility to cancer cells that allows adaptation to nutrient stress.

PubMed: 22999886
DOI: 10.1016/j.chembiol.2012.07.021

実験手法

X-RAY DIFFRACTION (2.3 Å)