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

DOI: 10.1107/S2059798318010380 DOI Help

Authors: Lucas Kraft (University of Sussex) , Mark Roe (University of Sussex) , Raj Gill (University of Sussex) , John Atack (Medicines Discovery Institute)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Acta Crystallographica Section D Structural Biology , VOL 74 , PAGES 973 - 978

State: Published (Approved)
Published: October 2018

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.

Journal Keywords: inositol monophosphatase; IMPase; lithium mimetic; L-690,330; bipolar disorder; lithium treatment

Diamond Keywords: Bipolar Disorder; Enzymes

Subject Areas: Medicine, Biology and Bio-materials

Instruments: I02-Macromolecular Crystallography , I04-Macromolecular Crystallography

Added On: 11/10/2018 14:14

Discipline Tags:

Life Sciences & Biotech Health & Wellbeing Drug Discovery Neurology Non-Communicable Diseases Structural biology

Technical Tags:

Diffraction Macromolecular Crystallography (MX)