Full-length human glutaminase in complex with an allosteric inhibitor.
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DeLaBarre B, Gross S, Fang C, Gao Y, Jha A, Jiang F, Song J J, Wei W, Hurov JB
Full-length human glutaminase in complex with an allosteric inhibitor.
Biochemistry. 2011 Dec 20;50(50):10764-70. doi: 10.1021/bi201613d. Epub 2011 Nov 18.
- PubMed ID
- 22049910 [ View in PubMed]
- 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.