Article ; Online: Full-length human glutaminase in complex with an allosteric inhibitor.
2011 Volume 50, Issue 50, Page(s) 10764–10770
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 ...
| 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. |
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| MeSH term(s) | Allosteric Site ; Amino Acid Sequence ; Amino Acid Substitution ; Biocatalysis ; Databases, Protein ; Dimerization ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/metabolism ; Glutaminase/antagonists & inhibitors ; Glutaminase/chemistry ; Glutaminase/genetics ; Glutaminase/metabolism ; Humans ; Isoenzymes/antagonists & inhibitors ; Isoenzymes/chemistry ; Isoenzymes/genetics ; Isoenzymes/metabolism ; Kinetics ; Models, Molecular ; Molecular Sequence Data ; Mutagenesis, Site-Directed ; Mutant Proteins/antagonists & inhibitors ; Mutant Proteins/chemistry ; Mutant Proteins/metabolism ; Point Mutation ; Protein Conformation ; Recombinant Proteins/antagonists & inhibitors ; Recombinant Proteins/chemistry ; Recombinant Proteins/metabolism ; Sequence Alignment ; Sulfides/chemistry ; Sulfides/metabolism ; Thiadiazoles/chemistry ; Thiadiazoles/metabolism | |||||
| Chemical Substances | Enzyme Inhibitors ; Isoenzymes ; Mutant Proteins ; Recombinant Proteins ; Sulfides ; Thiadiazoles ; bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide ; Glutaminase (EC 3.5.1.2) | |||||
| Language | English | |||||
| Publishing date | 2011-12-20 | |||||
| Publishing country | United States | |||||
| Document type | Journal Article ; Research Support, Non-U.S. Gov't | |||||
| ZDB-ID | 1108-3 | |||||
| ISSN | 1520-4995 ; 0006-2960 | |||||
| ISSN (online) | 1520-4995 | |||||
| ISSN | 0006-2960 | |||||
| DOI | 10.1021/bi201613d | |||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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