Co-crystallization of human inositol monophosphatase with the lithium mimetic L-690,330

Lucas Kraft, S. Mark Roe, Raj Gill, John R. Atack

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Abstract

Lithium, which is still the gold standard in the treatment of bipolar disorder, has been proposed to inhibit inositol monophosphatase (IMPase) and is hypothesized to exert its therapeutic effects by attenuating phosphatidylinositol (PI) cell signalling. Drug-discovery efforts have focused on small-molecule lithium mimetics that would specifically inhibit IMPase without exhibiting the undesired side effects of lithium. L-690,330 is a potent bisphosphonate substrate-based inhibitor developed by Merck Sharp & Dohme. To aid future structure-based inhibitor design, determination of the exact binding mechanism of L-690,330 to IMPase was of interest. Here, the high-resolution X-ray structure of human IMPase in complex with L690,330 and manganese ions determined at 1.39 Å resolution is reported.
Original languageEnglish
Pages (from-to)973-978
Number of pages6
JournalActa Crystallographica Section D Structural Biology
Volume74
Issue number10
DOIs
Publication statusPublished - 1 Oct 2018

Keywords

  • inositol monophosphatase
  • IMPase
  • lithium mimetic
  • L-690,330
  • bipolar disorder
  • lithum treatment

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