2bji

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(Difference between revisions)

Revision as of 05:50, 11 September 2015

HIGH RESOLUTION STRUCTURE OF MYO-INOSITOL MONOPHOSPHATASE, THE TARGET OF LITHIUM THERAPY

Structural highlights

2bji is a 2 chain structure with sequence from Bovin. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Activity:	Inositol-phosphate phosphatase, with EC number 3.1.3.25
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum

Function

[IMPA1_BOVIN] 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. Has broad substrate specificity and 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 (By similarity). Is equally active with myo-inositol monophosphate and D-galactose 1-phosphate.[UniProtKB:P29218]^[1]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

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).

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^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Parthasarathy R, Parthasarathy L, Vadnal R. Brain inositol monophosphatase identified as a galactose 1-phosphatase. Brain Res. 1997 Dec 5;778(1):99-106. PMID:9462881
↑ Gill R, Mohammed F, Badyal R, Coates L, Erskine P, Thompson D, Cooper J, Gore M, Wood S. High-resolution structure of myo-inositol monophosphatase, the putative target of lithium therapy. Acta Crystallogr D Biol Crystallogr. 2005 May;61(Pt 5):545-55. Epub 2005, Apr 20. PMID:15858264 doi:10.1107/S0907444905004038

1 Structural highlights
2 Function
3 Evolutionary Conservation
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2bji"

@@ Line 2: / Line 2: @@
 <StructureSection load='2bji' size='340' side='right' caption='[[2bji]], [[Resolution|resolution]] 1.24&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[2bji]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Bos_taurus Bos taurus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2BJI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2BJI FirstGlance]. <br>
+<table><tr><td colspan='2'>[[2bji]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Bovin Bovin]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2BJI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2BJI FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Inositol-phosphate_phosphatase Inositol-phosphate phosphatase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.3.25 3.1.3.25] </span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2bji FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2bji OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2bji RCSB], [http://www.ebi.ac.uk/pdbsum/2bji PDBsum]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2bji FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2bji OCA], [http://pdbe.org/2bji PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2bji RCSB], [http://www.ebi.ac.uk/pdbsum/2bji PDBsum]</span></td></tr>
 </table>
+== Function ==
+[[http://www.uniprot.org/uniprot/IMPA1_BOVIN IMPA1_BOVIN]] 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. Has broad substrate specificity and 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 (By similarity). Is equally active with myo-inositol monophosphate and D-galactose 1-phosphate.[UniProtKB:P29218]<ref>PMID:9462881</ref>
 == Evolutionary Conservation ==
 [[Image:Consurf_key_small.gif|200px|right]]
@@ Line 25: / Line 27: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 2bji" style="background-color:#fffaf0;"></div>
 ==See Also==
@@ Line 32: / Line 35: @@
 __TOC__
 </StructureSection>
-[[Category: Bos taurus]]
+[[Category: Bovin]]
 [[Category: Inositol-phosphate phosphatase]]
 [[Category: Badyal, R]]

2bji

From Proteopedia

Revision as of 05:50, 11 September 2015

HIGH RESOLUTION STRUCTURE OF MYO-INOSITOL MONOPHOSPHATASE, THE TARGET OF LITHIUM THERAPY

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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