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| | {{STRUCTURE_2bji| PDB=2bji | SCENE= }} | | {{STRUCTURE_2bji| PDB=2bji | SCENE= }} |
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| - | '''HIGH RESOLUTION STRUCTURE OF MYO-INOSITOL MONOPHOSPHATASE, THE TARGET OF LITHIUM THERAPY'''
| + | ===HIGH RESOLUTION STRUCTURE OF MYO-INOSITOL MONOPHOSPHATASE, THE TARGET OF LITHIUM THERAPY=== |
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| - | ==Overview==
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| - | Inositol monophosphatase is a key enzyme of the phosphatidylinositol signalling pathway and the putative target of the mood-stabilizing drug lithium. The crystal structure of bovine inositol monophosphatase has been determined at 1.4 A resolution in complex with the physiological magnesium ion ligands. Three magnesium ions are octahedrally coordinated at the active site of each of the two subunits of the inositol monophosphatase dimer and a detailed three-metal mechanism is proposed. Ligands to the three metals include the side chains of Glu70, Asp90, Asp93 and Asp220, the backbone carbonyl group of Ile92 and several solvent molecules, including the proposed nucleophilic water molecule (W1) ligated by both Mg-1 and Mg-3. Modelling of the phosphate moiety of inositol monophosphate to superpose the axial phosphate O atoms onto three active-site water molecules orientates the phosphoester bond for in-line attack by the nucleophilic water which is activated by Thr95. Modelling of the pentacoordinate transition state suggests that the 6-OH group of the inositol moiety stabilizes the developing negative charge by hydrogen bonding to a phosphate O atom. Modelling of the post-reaction complex suggests a role for a second water molecule (W2) ligated by Mg-2 and Asp220 in protonating the departing inositolate. This second water molecule is absent in related structures in which lithium is bound at site 2, providing a rationale for enzyme inhibition by this simple monovalent cation. The higher resolution structural information on the active site of inositol monophosphatase will facilitate the design of substrate-based inhibitors and aid in the development of better therapeutic agents for bipolar disorder (manic depression).
| + | The line below this paragraph, {{ABSTRACT_PUBMED_15858264}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 15858264 is the PubMed ID number. |
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| | + | {{ABSTRACT_PUBMED_15858264}} |
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| | ==About this Structure== | | ==About this Structure== |
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| | [[Category: Succinimide]] | | [[Category: Succinimide]] |
| | [[Category: Zymogen]] | | [[Category: Zymogen]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 20:22:33 2008'' | + | |
| | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 21:34:37 2008'' |
Revision as of 18:34, 28 July 2008
Template:STRUCTURE 2bji
HIGH RESOLUTION STRUCTURE OF MYO-INOSITOL MONOPHOSPHATASE, THE TARGET OF LITHIUM THERAPY
Template:ABSTRACT PUBMED 15858264
About this Structure
2BJI is a Single protein structure of sequence from Bos taurus. Full crystallographic information is available from OCA.
Reference
High-resolution structure of myo-inositol monophosphatase, the putative target of lithium therapy., Gill R, Mohammed F, Badyal R, Coates L, Erskine P, Thompson D, Cooper J, Gore M, Wood S, Acta Crystallogr D Biol Crystallogr. 2005 May;61(Pt 5):545-55. Epub 2005, Apr 20. PMID:15858264
Page seeded by OCA on Mon Jul 28 21:34:37 2008
