3SS4

Crystal structure of mouse Glutaminase C, phosphate-bound form

Summary for 3SS4

• Entry DOI: 10.2210/pdb3ss4/pdb
• Related: 3SS3 3SS5
• Descriptor: Glutaminase C, PHOSPHATE ION (3 entities in total)
• Functional Keywords: glutaminase, l-glutamine, mitochondria, hydrolase
• Biological source: Mus musculus (mouse)
• Total number of polymer chains: 4
• Total formula weight: 213687.73

Authors

Ambrosio, A.L.B.,Dias, S.M.G.,Cerione, R.A. (deposition date: 2011-07-07, release date: 2012-01-11, Last modification date: 2023-09-13)

Primary citation

Cassago, A.,Ferreira, A.P.,Ferreira, I.M.,Fornezari, C.,Gomes, E.R.,Greene, K.S.,Pereira, H.M.,Garratt, R.C.,Dias, S.M.,Ambrosio, A.L.
Mitochondrial localization and structure-based phosphate activation mechanism of Glutaminase C with implications for cancer metabolism.
Proc.Natl.Acad.Sci.USA, 109:1092-1097, 2012

PubMed Abstract: Glutamine is an essential nutrient for cancer cell proliferation, especially in the context of citric acid cycle anaplerosis. In this manuscript we present results that collectively demonstrate that, of the three major mammalian glutaminases identified to date, the lesser studied splice variant of the gene gls, known as Glutaminase C (GAC), is important for tumor metabolism. We show that, although levels of both the kidney-type isoforms are elevated in tumor vs. normal tissues, GAC is distinctly mitochondrial. GAC is also most responsive to the activator inorganic phosphate, the content of which is supposedly higher in mitochondria subject to hypoxia. Analysis of X-ray crystal structures of GAC in different bound states suggests a mechanism that introduces the tetramerization-induced lifting of a "gating loop" as essential for the phosphate-dependent activation process. Surprisingly, phosphate binds inside the catalytic pocket rather than at the oligomerization interface. Phosphate also mediates substrate entry by competing with glutamate. A greater tendency to oligomerize differentiates GAC from its alternatively spliced isoform and the cycling of phosphate in and out of the active site distinguishes it from the liver-type isozyme, which is known to be less dependent on this ion.

PubMed: 22228304
DOI: 10.1073/pnas.1112495109

Experimental method

X-RAY DIFFRACTION (2.85 Å)