2BJI

High Resolution Structure of myo-Inositol Monophosphatase, The Target of Lithium Therapy


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.24 Å
  • R-Value Free: 0.191 
  • R-Value Observed: 0.153 

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This is version 1.5 of the entry. See complete history


Literature

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.

(2005) Acta Crystallogr D Biol Crystallogr 61: 545-555

  • DOI: https://doi.org/10.1107/S0907444905004038
  • Primary Citation of Related Structures:  
    2BJI

  • PubMed Abstract: 

    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).


  • Organizational Affiliation

    Biomolecular Sciences Group, School of Biological Sciences, University of Southampton, Bassett Crescent East, Southampton SO16 7PX, England.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
INOSITOL-1(OR 4)-MONOPHOSPHATASE
A, B
277Bos taurusMutation(s): 0 
EC: 3.1.3.25
UniProt
Find proteins for P20456 (Bos taurus)
Explore P20456 
Go to UniProtKB:  P20456
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP20456
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.24 Å
  • R-Value Free: 0.191 
  • R-Value Observed: 0.153 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 47.23α = 67.22
b = 55.15β = 69.65
c = 60.88γ = 85.14
Software Package:
Software NamePurpose
SHELXL-97refinement
MOSFLMdata reduction
SCALAdata scaling
AMoREphasing

Structure Validation

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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2005-02-11
    Type: Initial release
  • Version 1.1: 2011-05-08
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2018-02-28
    Changes: Advisory, Database references, Source and taxonomy
  • Version 1.4: 2019-05-08
    Changes: Data collection, Experimental preparation
  • Version 1.5: 2023-12-13
    Changes: Advisory, Data collection, Database references, Derived calculations, Other, Refinement description