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PDBsum entry 1zsq
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References listed in PDB file
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Key reference
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Title
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Molecular basis for substrate recognition by mtmr2, A myotubularin family phosphoinositide phosphatase.
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Authors
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M.J.Begley,
G.S.Taylor,
M.A.Brock,
P.Ghosh,
V.L.Woods,
J.E.Dixon.
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Ref.
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Proc Natl Acad Sci U S A, 2006,
103,
927-932.
[DOI no: ]
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PubMed id
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Abstract
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Myotubularins, a large family of catalytically active and inactive proteins,
belong to a unique subgroup of protein tyrosine phosphatases that use inositol
phospholipids, rather than phosphoproteins, as physiological substrates. Here,
by integrating crystallographic and deuterium-exchange mass spectrometry studies
of human myotubularin-related protein-2 (MTMR2) in complex with
phosphoinositides, we define the molecular basis for this unique substrate
specificity. Phosphoinositide substrates bind in a pocket located on a
positively charged face of the protein, suggesting an electrostatic mechanism
for membrane targeting. A flexible, hydrophobic helix makes extensive
interactions with the diacylglycerol moieties of substrates, explaining the
specificity for membrane-bound phosphoinositides. An extensive H-bonding network
and charge-charge interactions within the active site pocket determine
phosphoinositide headgroup specificity. The conservation of these specificity
determinants within the active, but not the inactive, myotubularins provides
insight into the functional differences between the active and inactive members.
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Figure 1.
Fig. 1. MTMR2 structure. (A) Domain organization of MTMR2.
(B) Ribbon diagram of MTMR2 [PI(3,5)P[2] complex] in two
orientations. Bound substrate is shown in stick form. Figure was
created using PYMOL (DeLano Scientific, South San Francisco, CA;
http://pymol.sourceforge.net).
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Figure 4.
Fig. 4. PI specificity. (A) Slices of active-site surfaces
showing the MTMR2 pocket in comparison with VHR and PTP1B. (B)
Slices of the active-site surfaces of superimposed MTMR2-PI(3)P
and MTMR2-PI(3,5)P[2] models. Substrates are shown as sticks,
and a water molecule seen in the MTMR2-PI(3)P structure is shown
as a green sphere. (C and D) Active-site surface colored by
electrostatic potential. Saturating blue and red are 10 and -10
kT/e, respectively. Bound PI(3,5)P[2] is shown as a stick. The
interaction between the diacylglycerol moiety and helix  6(C) and
solvent-exposed hydrophobic residues on helix 6(D) are
shown. (E and F) The PI(3,5)P[2] (E) and PI(3)P (F) active
sites. The phosphatase domain is shown in blue, side chains
interacting with the ligands are shown as sticks, and water
molecules are red spheres. H-bonds and salt bridges are shown as
dashed lines. Several H-bonds between the substrates and water
molecules have been omitted for clarity.
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