Co‐crystallization of human inositol monophosphatase with the lithium mimetic L‐690, 330. Issue 10 (5th October 2018)

• Record Type: Journal Article
• Authors: Kraft, Lucas; Roe, S. Mark; Gill, Raj; Atack, John R.
• Is Part Of: Acta crystallographica. Volume 74:Issue 10(2018)
• Page Start: 973
• Page End: 978
• Publication Date: 2018-10-05
• Subjects: inositol monophosphatase -- IMPase -- lithium mimetic -- L‐690, 330 -- bioplar disorder -- lithium treatment; X-ray crystallography -- Periodicals; Crystallography -- Periodicals; Molecular biology -- Periodicals; Molecular structure -- Periodicals; Biomolecules -- Structure -- Periodicals; Cytology -- Periodicals; Biomolecules -- Structure; Crystallography; Cytology; Molecular biology; Molecular structure; X-ray crystallography; Periodicals; 548
• DOI: 10.1107/S2059798318010380
• Languages: English
• ISSNs: 2059-7983

Abstract

Abstract : The crystal structure of human inositol monophosphatase in complex with the substrate‐based inhibitor L‐690, 330 is reported. 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.