6giu
Human IMPase with L-690330Human IMPase with L-690330
Structural highlights
Function[IMPA1_HUMAN] Responsible for the provision of inositol required for synthesis of phosphatidylinositol and polyphosphoinositides and has been implicated as the pharmacological target for lithium action in brain. Can use myo-inositol monophosphates, myo-inositol 1,3-diphosphate, myo-inositol 1,4-diphosphate, scyllo-inositol-phosphate, glucose-1-phosphate, glucose-6-phosphate, fructose-1-phosphate, beta-glycerophosphate, and 2'-AMP as substrates.[1] Publication Abstract from PubMedLithium, 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 A resolution is reported. Co-crystallization of human inositol monophosphatase with the lithium mimetic L-690,330.,Kraft L, Roe SM, Gill R, Atack JR Acta Crystallogr D Struct Biol. 2018 Oct 1;74(Pt 10):973-978. doi:, 10.1107/S2059798318010380. Epub 2018 Oct 2. PMID:30289407[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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