title: Full-length human glutaminase in complex with an allosteric inhibitor.
abstract: Glutaminase (GLS1/2) catalyzes the conversion of L-glutamine to L-glutamate and ammonia. The level of a splice variant of GLS1 (GAC) is elevated in certain cancers, and GAC is specifically inhibited by bis-2-(5-phenylacetimido-1,2,4,thiadiazol-2-yl)ethyl sulfide (BPTES). We report here the first full-length crystal structure of GAC in the presence and absence of BPTES molecules. Two BPTES molecules bind at an interface region of the GAC tetramer in a manner that appears to lock the GAC tetramer into a nonproductive conformation. The importance of these loops with regard to overall enzymatic activity of the tetramer was revealed by a series of GAC point mutants designed to create a BPTES resistant GAC.
authors: Agios Pharmaceuticals, Cambridge, Massachusetts 02139-4169, United States. byron.delabarre@agios.com
authors: Byron
authors: B
authors: DeLaBarre
authors: Stefan
authors: S
authors: Gross
authors: Cheng
authors: C
authors: Fang
authors: Yi
authors: Y
authors: Gao
authors: Abhishek
authors: A
authors: Jha
authors: Fan
authors: F
authors: Jiang
authors: Juanhua
authors: J
authors: Song J
authors: Wentao
authors: W
authors: Wei
authors: Jonathan B
authors: JB
authors: Hurov
mesh_terms: D000495:Allosteric Site; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D055162:Biocatalysis; D030562:Databases, Protein; D019281:Dimerization; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism*; D005972:Glutaminase / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D050505:Mutant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D017354:Point Mutation; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D016415:Sequence Alignment; D013440:Sulfides / Q000737:chemistry / Q000378:metabolism; D013830:Thiadiazoles / Q000737:chemistry / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D007527:Isoenzymes; D050505:Mutant Proteins; D011994:Recombinant Proteins; D013440:Sulfides; D013830:Thiadiazoles; C523193:bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide; D005972:Glutaminase