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PDBsum entry 1zvr

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protein ligands links
Hydrolase PDB id
1zvr
Jmol
Contents
Protein chain
514 a.a. *
Ligands
EDO ×3
3PI
Waters ×398
* Residue conservation analysis
PDB id:
1zvr
Name: Hydrolase
Title: Crystal structure of mtmr2 in complex with phosphatidylinositol 3,5-bisphosphate
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:
1.98Å     R-factor:   0.228     R-free:   0.252
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:
02-Jun-05     Release date:   31-Jan-06    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q13614  (MTMR2_HUMAN) -  Myotubularin-related protein 2
Seq:
Struc:
 
Seq:
Struc:
643 a.a.
514 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     dephosphorylation   1 term 
  Biochemical function     phosphatase activity     1 term  

 

 
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.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21291543 F.Liu, J.A.White, C.Antonescu, D.Gusenleitner, and J.Quackenbush (2011).
GCOD - GeneChip Oncology Database.
  BMC Bioinformatics, 12, 46.  
21342575 S.Liu, L.Liu, U.Uzuner, X.Zhou, M.Gu, W.Shi, Y.Zhang, S.Y.Dai, and J.S.Yuan (2011).
HDX-analyzer: a novel package for statistical analysis of protein structure dynamics.
  BMC Bioinformatics, 12, S43.  
20967218 I.Ndamukong, D.R.Jones, H.Lapko, N.Divecha, and Z.Avramova (2010).
Phosphatidylinositol 5-phosphate links dehydration stress to the activity of ARABIDOPSIS TRITHORAX-LIKE factor ATX1.
  PLoS One, 5, e13396.  
19913036 Q.Xu, A.Bateman, R.D.Finn, P.Abdubek, T.Astakhova, H.L.Axelrod, C.Bakolitsa, D.Carlton, C.Chen, H.J.Chiu, M.Chiu, T.Clayton, D.Das, M.C.Deller, L.Duan, K.Ellrott, D.Ernst, C.L.Farr, J.Feuerhelm, J.C.Grant, A.Grzechnik, G.W.Han, L.Jaroszewski, K.K.Jin, H.E.Klock, M.W.Knuth, P.Kozbial, S.S.Krishna, A.Kumar, D.Marciano, D.McMullan, M.D.Miller, A.T.Morse, E.Nigoghossian, A.Nopakun, L.Okach, C.Puckett, R.Reyes, C.L.Rife, N.Sefcovic, H.J.Tien, C.B.Trame, H.van den Bedem, D.Weekes, T.Wooten, K.O.Hodgson, J.Wooley, M.A.Elsliger, A.M.Deacon, A.Godzik, S.A.Lesley, and I.A.Wilson (2010).
Bacterial pleckstrin homology domains: a prokaryotic origin for the PH domain.
  J Mol Biol, 396, 31-46.
PDB codes: 3b77 3dcx 3hsa
20122183 S.Mitra, M.Schubach, and D.H.Huson (2010).
Short clones or long clones? A simulation study on the use of paired reads in metagenomics.
  BMC Bioinformatics, 11, S12.  
20946595 U.Uzuner, W.Shi, L.Liu, S.Liu, S.Y.Dai, and J.S.Yuan (2010).
Enzyme structure dynamics of xylanase I from Trichoderma longibrachiatum.
  BMC Bioinformatics, 11, S12.  
19810703 D.Vidović, and S.C.Schürer (2009).
Knowledge-based characterization of similarity relationships in the human protein-tyrosine phosphatase family for rational inhibitor design.
  J Med Chem, 52, 6649-6659.  
19754155 S.Hsu, Y.Kim, S.Li, E.S.Durrant, R.M.Pace, V.L.Woods, and M.S.Gentry (2009).
Structural insights into glucan phosphatase dynamics using amide hydrogen-deuterium exchange mass spectrometry.
  Biochemistry, 48, 9891-9902.  
19580826 T.Sasaki, S.Takasuga, J.Sasaki, S.Kofuji, S.Eguchi, M.Yamazaki, and A.Suzuki (2009).
Mammalian phosphoinositide kinases and phosphatases.
  Prog Lipid Res, 48, 307-343.  
  19901554 Y.Ding, H.Lapko, I.Ndamukong, Y.Xia, A.Al-Abdallat, S.Lalithambika, M.Sadder, A.Saleh, M.Fromm, J.J.Riethoven, G.Lu, and Z.Avramova (2009).
The Arabidopsis chromatin modifier ATX1, the myotubularin-like AtMTM and the response to drought.
  Plant Signal Behav, 4, 1049-1058.  
17973976 D.Goryunov, A.Nightingale, L.Bornfleth, C.Leung, and R.K.Liem (2008).
Multiple disease-linked myotubularin mutations cause NFL assembly defects in cultured cells and disrupt myotubularin dimerization.
  J Neurochem, 104, 1536-1552.  
18433060 D.J.Aceti, E.Bitto, A.F.Yakunin, M.Proudfoot, C.A.Bingman, R.O.Frederick, H.K.Sreenath, F.C.Vojtik, R.L.Wrobel, B.G.Fox, J.L.Markley, and G.N.Phillips (2008).
Structural and functional characterization of a novel phosphatase from the Arabidopsis thaliana gene locus At1g05000.
  Proteins, 73, 241-253.
PDB code: 1xri
18298792 R.Pulido, and R.Hooft van Huijsduijnen (2008).
Protein tyrosine phosphatases: dual-specificity phosphatases in health and disease.
  FEBS J, 275, 848-866.  
17917119 A.Bolis, P.Zordan, S.Coviello, and A.Bolino (2007).
Myotubularin-related (MTMR) phospholipid phosphatase proteins in the peripheral nervous system.
  Mol Neurobiol, 35, 308-316.  
17154432 A.K.Hirsch, F.R.Fischer, and F.Diederich (2007).
Phosphate recognition in structural biology.
  Angew Chem Int Ed Engl, 46, 338-352.  
17603894 A.L.Lomize, I.D.Pogozheva, M.A.Lomize, and H.I.Mosberg (2007).
The role of hydrophobic interactions in positioning of peripheral proteins in membranes.
  BMC Struct Biol, 7, 44.  
17572665 C.Y.Chow, Y.Zhang, J.J.Dowling, N.Jin, M.Adamska, K.Shiga, K.Szigeti, M.E.Shy, J.Li, X.Zhang, J.R.Lupski, L.S.Weisman, and M.H.Meisler (2007).
Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J.
  Nature, 448, 68-72.  
17605038 D.Blero, B.Payrastre, S.Schurmans, and C.Erneux (2007).
Phosphoinositide phosphatases in a network of signalling reactions.
  Pflugers Arch, 455, 31-44.  
17342524 M.Golynskiy, S.Li, V.L.Woods, and S.M.Cohen (2007).
Conformational studies of the manganese transport regulator (MntR) from Bacillus subtilis using deuterium exchange mass spectrometry.
  J Biol Inorg Chem, 12, 699-709.  
17057753 N.K.Tonks (2006).
Protein tyrosine phosphatases: from genes, to function, to disease.
  Nat Rev Mol Cell Biol, 7, 833-846.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.