PDBsum entry 1lw3

Hydrolase

PDB id: 1lw3

Contents

Protein chain

513 a.a. *

Ligands

PO4 ×3

Waters ×274

* Residue conservation analysis

PDB id:

1lw3

Name:

Hydrolase

Title:

Crystal structure of myotubularin-related protein 2 complexed with phosphate

Structure:

Myotubularin-related protein 2. Chain: a. Fragment: ph and phosphatase domains (residues 1-643). Engineered: yes. Mutation: yes

Source:

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

Resolution:

2.30Å R-factor: 0.209 R-free: 0.273

Authors:

M.J.Begley,G.S.Taylor,S.-A.Kim,D.M.Veine,J.E.Dixon,J.A.Stuckey

Key ref:

M.J.Begley et al. (2003). Crystal structure of a phosphoinositide phosphatase, MTMR2: insights into myotubular myopathy and Charcot-Marie-Tooth syndrome. Mol Cell, 12, 1391-1402. PubMed id: 14690594 DOI: 10.1016/S1097-2765(03)00486-6

Date:

30-May-02 Release date: 07-Oct-03

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

1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3-phosphate) + H2O = 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol) + phosphate (Bound ligand (Het Group name = PO4) corresponds exactly)

• 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

1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3,5-bisphosphate) + H2O = 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-5-phosphate) + phosphate (Bound ligand (Het Group name = PO4) corresponds exactly)

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: 10.1016/S1097-2765(03)00486-6

Mol Cell 12:1391-1402 (2003)

PubMed id: 14690594

Crystal structure of a phosphoinositide phosphatase, MTMR2: insights into myotubular myopathy and Charcot-Marie-Tooth syndrome.

M.J.Begley, G.S.Taylor, S.A.Kim, D.M.Veine, J.E.Dixon, J.A.Stuckey.

ABSTRACT

Myotubularin-related proteins are a large subfamily of protein tyrosine phosphatases (PTPs) that dephosphorylate D3-phosphorylated inositol lipids. Mutations in members of the myotubularin family cause the human neuromuscular disorders myotubular myopathy and type 4B Charcot-Marie-Tooth syndrome. The crystal structure of a representative member of this family, MTMR2, reveals a phosphatase domain that is structurally unique among PTPs. A series of mutants are described that exhibit altered enzymatic activity and provide insight into the specificity of myotubularin phosphatases toward phosphoinositide substrates. The structure also reveals that the GRAM domain, found in myotubularin family phosphatases and predicted to occur in approximately 180 proteins, is part of a larger motif with a pleckstrin homology (PH) domain fold. Finally, the MTMR2 structure will serve as a model for other members of the myotubularin family and provide a framework for understanding the mechanism whereby mutations in these proteins lead to disease.

Selected figure(s)

Figure 5.
Figure 5. Model of Ins(1,3,5)P[3] in the Active Site of MTMR2(A) A schematic of the phosphate molecules and hydrogen bond network in the MTMR2 active site. Hydrogen bonds are shown as blue dotted lines.(B) Model of Ins(1,3,5)P[3] in the active site of MTMR2 with its D1 and D3 phosphate groups superimposed onto the phosphate molecules shown in (A).(C) Phosphatase activity of MTMR2 mutants toward PI(3)P and PI(3,5)P[2] substrates. Values are expressed as percent wild-type MTMR2 activity of three independent experiments (mean ± SEM).

Figure 6.
Figure 6. Missense Disease Mutations(A) Sequence conservation of MTM1 and MTMR2 and the location of missense disease mutations. The sequence of MTMR2 corresponding to the crystal structure was aligned with MTM1. Regions of identity are boxed and shaded. Arrows and ovals represent β strands and α helices, respectively. Missense disease mutations are marked with arrowheads.(B) Van der Waals surface space-filled model of MTMR2. The view is the same as Figure 2A. The PH-GRAM domain is shown in green, the phosphatase domain in blue, and the active site motif (P loop) in yellow. Residues that are sites of missense disease mutations are red and labeled when >10% solvent accessible.(C) View corresponding to a 180° rotation around a vertical axis with respect to Figure 6B. Solvent accessible residues are indicated.

The above figures are reprinted by permission from Cell Press: Mol Cell (2003, 12, 1391-1402) copyright 2003.

Figures were selected by an automated process.