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Full-Length Human Glutaminase in Complex with an Allosteric Inhibitor

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journal contribution
posted on 20.12.2011, 00:00 by Byron DeLaBarre, Stefan Gross, Cheng Fang, Yi Gao, Abhishek Jha, Fan Jiang, Juanhua Song J., Wentao Wei, Jonathan B. Hurov
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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