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000612788 1001_ $$0P:(DE-HGF)0$$aMehlman, Tamar$$b0
000612788 245__ $$aAn expanded trove of fragment-bound structures for the allosteric enzyme PTP1B from computational reanalysis of large-scale crystallographic data
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000612788 520__ $$aDue to their low binding affinities, detecting small-molecule fragments bound to protein structures from crystallographic datasets has been a challenge. Here, we report a trove of 65 new fragment hits for PTP1B, an “undruggable” therapeutic target enzyme for diabetes and cancer. These structures were obtained from computational analysis of data from a large crystallographic screen, demonstrating the power of this approach to elucidate many (∼50% more) “hidden” ligand-bound states of proteins. Our new structures include a fragment hit found in a novel binding site in PTP1B with a unique location relative to the active site, one that links adjacent allosteric sites, and, perhaps most strikingly, a fragment that induces long-range allosteric protein conformational responses. Altogether, our research highlights the utility of computational analysis of crystallographic data, makes publicly available dozens of new ligand-bound structures of a high-value drug target, and identifies novel aspects of ligandability and allostery in PTP1B.
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000612788 7001_ $$0P:(DE-H253)PIP1032871$$aGinn, Helen M.$$b1
000612788 7001_ $$00000-0002-9184-7586$$aKeedy, Daniel A.$$b2$$eCorresponding author
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