4G1N

PKM2 in complex with an activator

Summary for 4G1N

• Entry DOI: 10.2210/pdb4g1n/pdb
• Descriptor: Pyruvate kinase isozymes M1/M2, OXALATE ION, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: pyruvate kinase, aerobic glycolysis, activator, cancer metabolism, phosphorylation of pyruvate, transferase-activator complex, transferase/activator
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P14618
• Total number of polymer chains: 4
• Total formula weight: 228027.52

Authors

Kung, C.,Hixon, J.,Dang, L.,DeLaBarre, B.,Qian, K.C. (deposition date: 2012-07-10, release date: 2012-10-10, Last modification date: 2024-02-28)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.3 Å)