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

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

doi:10.1107/S2059798318010380

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

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

School of Biological Sciences

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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 language	English
Pages (from-to)	973-978
Number of pages	6
Journal	Acta Crystallographica Section D Structural Biology
Volume	74
Issue number	10
DOIs	https://doi.org/10.1107/S2059798318010380
Publication status	Published - 1 Oct 2018

Keywords

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

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10.1107/S2059798318010380

Structural insight into inositol monophosphatase
This is the author's accepted manuscript of Lucas Kraft, et al. 'Co-crystallization of human inositol monophosphatase with the lithium mimetic L-690,330,' Acta Crystallographica Section D: Structural Biology, 74 (10), October 2018, pp. 973-978. The final published version can be found at https://doi.org/10.1107/S2059798318010380.
Accepted author manuscript (Post-print), 879 KB

Cite this

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

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 {\AA} resolution is reported.",

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AU - Roe, S. Mark

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AB - 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.

KW - inositol monophosphatase

KW - IMPase

KW - lithium mimetic

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KW - bipolar disorder

KW - lithum treatment

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

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Keywords

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