4JKT

Crystal structure of mouse Glutaminase C, BPTES-bound form

4JKT の概要

• エントリーDOI: 10.2210/pdb4jkt/pdb
• 関連するPDBエントリー: 3SS3 3SS4 3SS5
• 分子名称: Glutaminase kidney isoform, mitochondrial, N,N'-[sulfanediylbis(ethane-2,1-diyl-1,3,4-thiadiazole-5,2-diyl)]bis(2-phenylacetamide) (3 entities in total)
• 機能のキーワード: glutaminase, hydrolase
• 由来する生物種: Mus musculus (mouse)
• 細胞内の位置: Isoform 1: Cytoplasm, cytosol . Isoform 2: Mitochondrion: D3Z7P3
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 214357.21

構造登録者

Fornezari, C.,Ferreira, A.P.S.,Dias, S.M.G.,Ambrosio, A.L.B. (登録日: 2013-03-11, 公開日: 2013-08-14, 最終更新日: 2023-09-20)

主引用文献

Ferreira, A.P.,Cassago, A.,Goncalves Kde, A.,Dias, M.M.,Adamoski, D.,Ascencao, C.F.,Honorato, R.V.,de Oliveira, J.F.,Ferreira, I.M.,Fornezari, C.,Bettini, J.,Oliveira, P.S.,Paes Leme, A.F.,Portugal, R.V.,Ambrosio, A.L.,Dias, S.M.
Active Glutaminase C Self-assembles into a Supratetrameric Oligomer That Can Be Disrupted by an Allosteric Inhibitor.
J.Biol.Chem., 288:28009-28020, 2013

PubMed Abstract: The phosphate-dependent transition between enzymatically inert dimers into catalytically capable tetramers has long been the accepted mechanism for the glutaminase activation. Here, we demonstrate that activated glutaminase C (GAC) self-assembles into a helical, fiber-like double-stranded oligomer and propose a molecular model consisting of seven tetramer copies per turn per strand interacting via the N-terminal domains. The loop (321)LRFNKL(326) is projected as the major regulating element for self-assembly and enzyme activation. Furthermore, the previously identified in vivo lysine acetylation (Lys(311) in humans, Lys(316) in mouse) is here proposed as an important down-regulator of superoligomer assembly and protein activation. Bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide, a known glutaminase inhibitor, completely disrupted the higher order oligomer, explaining its allosteric mechanism of inhibition via tetramer stabilization. A direct correlation between the tendency to self-assemble and the activity levels of the three mammalian glutaminase isozymes was established, with GAC being the most active enzyme while forming the longest structures. Lastly, the ectopic expression of a fiber-prone superactive GAC mutant in MDA-MB 231 cancer cells provided considerable proliferative advantages to transformed cells. These findings yield unique implications for the development of GAC-oriented therapeutics targeting tumor metabolism.

PubMed: 23935106
DOI: 10.1074/jbc.M113.501346

実験手法

X-RAY DIFFRACTION (2.77 Å)