PDBsum entry 1zsq

Hydrolase

PDB id: 1zsq

Contents

Protein chain

513 a.a. *

Ligands

EDO ×4

PIB

Waters ×399

* Residue conservation analysis

PDB id:

1zsq

Name:

Hydrolase

Title:

Crystal structure of mtmr2 in complex with phosphatidylinositol 3- phosphate

Structure:

Myotubularin-related protein 2. Chain: a. Fragment: ph-gram and phosphatase domains. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: mtmr2, kiaa1073. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

Resolution:

1.82Å R-factor: 0.218 R-free: 0.243

Authors:

M.J.Begley,G.S.Taylor,M.A.Brock,P.Ghosh,V.L.Woods,J.E.Dixon

Key ref:

M.J.Begley et al. (2006). Molecular basis for substrate recognition by MTMR2, a myotubularin family phosphoinositide phosphatase. Proc Natl Acad Sci U S A, 103, 927-932. PubMed id: 16410353 DOI: 10.1073/pnas.0510006103

Date:

25-May-05 Release date: 31-Jan-06

Protein chain

Q13614  (MTMR2_HUMAN) -  Myotubularin-related protein 2 from Homo sapiens

Seq: 643 a.a.

Struc: 513 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class 2: E.C.3.1.3.64 - phosphatidylinositol-3-phosphatase.
• Reaction: a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3-phosphate) + H2O = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol) + phosphate
• Enzyme class 3: E.C.3.1.3.95 - phosphatidylinositol-3,5-bisphosphate 3-phosphatase.
• Reaction: a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3,5-bisphosphate) + H2O = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-5-phosphate) + phosphate

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1073/pnas.0510006103

Proc Natl Acad Sci U S A 103:927-932 (2006)

PubMed id: 16410353

Molecular basis for substrate recognition by MTMR2, a myotubularin family phosphoinositide phosphatase.

M.J.Begley, G.S.Taylor, M.A.Brock, P.Ghosh, V.L.Woods, J.E.Dixon.

ABSTRACT

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.

Selected figure(s)

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).

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.

Figures were selected by an automated process.