3U2Z

Activator-Bound Structure of Human Pyruvate Kinase M2

3U2Z の概要

• エントリーDOI: 10.2210/pdb3u2z/pdb
• 分子名称: Pyruvate kinase isozymes M1/M2, 1,6-di-O-phosphono-beta-D-fructofuranose, UNKNOWN ATOM OR ION, ... (5 entities in total)
• 機能のキーワード: transferase, structural genomics, structural genomics consortium, sgc, transferase-transferase activator complex, transferase/transferase activator
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 234749.33

構造登録者

Hong, B.,Dimov, S.,Tempel, W.,Auld, D.,Thomas, C.,Boxer, M.,Jianq, J.-K.,Skoumbourdis, A.,Min, S.,Southall, N.,Arrowsmith, C.H.,Edwards, A.M.,Bountra, C.,Weigelt, J.,Inglese, J.,Park, H.,Structural Genomics Consortium (SGC) (登録日: 2011-10-04, 公開日: 2012-09-12, 最終更新日: 2023-09-13)

主引用文献

Anastasiou, D.,Yu, Y.,Israelsen, W.J.,Jiang, J.K.,Boxer, M.B.,Hong, B.S.,Tempel, W.,Dimov, S.,Shen, M.,Jha, A.,Yang, H.,Mattaini, K.R.,Metallo, C.M.,Fiske, B.P.,Courtney, K.D.,Malstrom, S.,Khan, T.M.,Kung, C.,Skoumbourdis, A.P.,Veith, H.,Southall, N.,Walsh, M.J.,Brimacombe, K.R.,Leister, W.,Lunt, S.Y.,Johnson, Z.R.,Yen, K.E.,Kunii, K.,Davidson, S.M.,Christofk, H.R.,Austin, C.P.,Inglese, J.,Harris, M.H.,Asara, J.M.,Stephanopoulos, G.,Salituro, F.G.,Jin, S.,Dang, L.,Auld, D.S.,Park, H.W.,Cantley, L.C.,Thomas, C.J.,Vander Heiden, M.G.
Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis.
Nat.Chem.Biol., 8:839-847, 2012

PubMed Abstract: Cancer cells engage in a metabolic program to enhance biosynthesis and support cell proliferation. The regulatory properties of pyruvate kinase M2 (PKM2) influence altered glucose metabolism in cancer. The interaction of PKM2 with phosphotyrosine-containing proteins inhibits enzyme activity and increases the availability of glycolytic metabolites to support cell proliferation. This suggests that high pyruvate kinase activity may suppress tumor growth. We show that expression of PKM1, the pyruvate kinase isoform with high constitutive activity, or exposure to published small-molecule PKM2 activators inhibits the growth of xenograft tumors. Structural studies reveal that small-molecule activators bind PKM2 at the subunit interaction interface, a site that is distinct from that of the endogenous activator fructose-1,6-bisphosphate (FBP). However, unlike FBP, binding of activators to PKM2 promotes a constitutively active enzyme state that is resistant to inhibition by tyrosine-phosphorylated proteins. These data support the notion that small-molecule activation of PKM2 can interfere with anabolic metabolism.

PubMed: 22922757
DOI: 10.1038/nchembio.1060

実験手法

X-RAY DIFFRACTION (2.1 Å)