4jkt

Crystal structure of mouse Glutaminase C, BPTES-bound form

spinqualitylabelsall models 4jkt, resolution 2.77Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4jkt is a 4 chain structure with sequence from Lk3 transgenic mice. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 04A Related: 3ss3, 3ss4, 3ss5 Gene: Gls, Gls1, Kiaa0838 (LK3 transgenic mice) Activity: Glutaminase, with EC number 3.5.1.2 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [GLSK_MOUSE] Catalyzes the first reaction in the primary pathway for the renal catabolism of glutamine. Plays a role in maintaining acid-base homeostasis. Regulates the levels of the neurotransmitter glutamate in the brain. Publication Abstract from PubMed The phosphate-dependent transition between enzimatically 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 L321RFNKL326 is projected as the major regulating element for self-assembly and enzyme activation. Furthermore, the previously identified in vivo lysine acetylation (Lys311 in humans, Lys316 in mouse) is here proposed as an important down-regulator of super-oligomer assembly and protein activation. BPTES (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 more active enzyme while forming the longest structures. Lastly, the ectopic expression of a fiber-prone super-active 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. Active Glutaminase C self-assembles into a supra-tetrameric oligomer which can be disrupted by an allosteric inhibitor.,Ferreira AP, Cassago A, Goncalves KA, Dias MM, Adamoski D, Ascencao CF, Honorato RV, de Oliveira JF, Ferreira IM, Fornezari C, Bettini J, Oliveira PS, Paes Leme AF, Portugal RV, Ambrosio AL, Dias SM J Biol Chem. 2013 Aug 8. PMID:23935106 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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