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PDBsum entry 1vhr
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Hydrolase PDB id
1vhr

 

 

 

 

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Contents
Protein chains
178 a.a. *
Ligands
EPE
SO4
Waters ×141
* Residue conservation analysis
PDB id:
1vhr
Name: Hydrolase
Title: Human vh1-related dual-specificity phosphatase
Structure: Human vh1-related dual-specificity phosphatase vhr. Chain: a, b. Synonym: vhr. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Other_details: original gene gdb\:dusp3. Vhr, chromosome map position 17q21
Resolution:
2.10Å     R-factor:   0.176     R-free:   0.254
Authors: J.Yuvaniyama,J.M.Denu,J.E.Dixon,M.A.Saper
Key ref: J.Yuvaniyama et al. (1996). Crystal structure of the dual specificity protein phosphatase VHR. Science, 272, 1328-1331. PubMed id: 8650541 DOI: 10.1126/science.272.5266.1328
Date:
20-Feb-96     Release date:   20-Jun-96    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P51452  (DUS3_HUMAN) -  Dual specificity protein phosphatase 3 from Homo sapiens
Seq:
Struc: 		185 a.a.
178 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class 2: E.C.3.1.3.16  - protein-serine/threonine phosphatase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction:
1. O-phospho-L-seryl-[protein] + H2O = L-seryl-[protein] + phosphate
2. O-phospho-L-threonyl-[protein] + H2O = L-threonyl-[protein] + phosphate
O-phospho-L-seryl-[protein]
 + H2O
 = L-seryl-[protein]
 + phosphate
O-phospho-L-threonyl-[protein]
 + H2O
 = L-threonyl-[protein]
 + phosphate
   Enzyme class 3: E.C.3.1.3.48  - protein-tyrosine-phosphatase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: O-phospho-L-tyrosyl-[protein] + H2O = L-tyrosyl-[protein] + phosphate
O-phospho-L-tyrosyl-[protein]
 + H2O
 = L-tyrosyl-[protein]
 + 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

 

 
    reference    
 
 
DOI no: 10.1126/science.272.5266.1328 Science 272:1328-1331 (1996)
PubMed id: 8650541  
 
 
Crystal structure of the dual specificity protein phosphatase VHR.
J.Yuvaniyama, J.M.Denu, J.E.Dixon, M.A.Saper.
 
  ABSTRACT  
 
Dual specificity protein phosphatases (DSPs) regulate mitogenic signal transduction and control the cell cycle. Here, the crystal structure of a human DSP, vaccinia H1-related phosphatase (or VHR), was determined at 2.1 angstrom resolution. A shallow active site pocket in VHR allows for the hydrolysis of phosphorylated serine, threonine, or tyrosine protein residues, whereas the deeper active site of protein tyrosine phosphatases (PTPs) restricts substrate specificity to only phosphotyrosine. Positively charged crevices near the active site may explain the enzyme's preference for substrates with two phosphorylated residues. The VHR structure defines a conserved structural scaffold for both DSPs and PTPs. A "recognition region," connecting helix alpha1 to strand beta1, may determine differences in substrate specificity between VHR, the PTPs, and other DSPs.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21409566 C.Romá-Mateo, A.Sacristán-Reviriego, N.J.Beresford, J.A.Caparrós-Martín, F.A.Culiáñez-Macià, H.Martín, M.Molina, L.Tabernero, and R.Pulido (2011).
Phylogenetic and genetic linkage between novel atypical dual-specificity phosphatases from non-metazoan organisms.
  Mol Genet Genomics, 285, 341-354.  
21391303 G.Hirai, A.Tsuchiya, Y.Koyama, Y.Otani, K.Oonuma, K.Dodo, S.Simizu, H.Osada, and M.Sodeoka (2011).
Development of a Vaccinia H1-related (VHR) phosphatase inhibitor with a nonacidic phosphate-mimicking core structure.
  ChemMedChem, 6, 617-622.  
21543850 G.T.Lountos, J.E.Tropea, and D.S.Waugh (2011).
Structure of human dual-specificity phosphatase 27 at 2.38 Å resolution.
  Acta Crystallogr D Biol Crystallogr, 67, 471-479.
PDB code: 2y96
20679247 C.W.Vander Kooi, A.O.Taylor, R.M.Pace, D.A.Meekins, H.F.Guo, Y.Kim, and M.S.Gentry (2010).
Structural basis for the glucan phosphatase activity of Starch Excess4.
  Proc Natl Acad Sci U S A, 107, 15379-15384.
PDB code: 3nme
20018849 J.P.Li, Y.N.Fu, Y.R.Chen, and T.H.Tan (2010).
JNK pathway-associated phosphatase dephosphorylates focal adhesion kinase and suppresses cell migration.
  J Biol Chem, 285, 5472-5478.  
19211553 A.C.Koksal, J.D.Nardozzi, and G.Cingolani (2009).
Dimeric quaternary structure of the prototypical dual specificity phosphatase VH1.
  J Biol Chem, 284, 10129-10137.
PDB code: 3cm3
19415758 D.G.Jeong, S.K.Jung, T.S.Yoon, E.J.Woo, J.H.Kim, B.C.Park, S.E.Ryu, and S.J.Kim (2009).
Crystal structure of the catalytic domain of human MKP-2 reveals a 24-mer assembly.
  Proteins, 76, 763-767.
PDB code: 3ezz
19770498 G.T.Lountos, J.E.Tropea, S.Cherry, and D.S.Waugh (2009).
Overproduction, purification and structure determination of human dual-specificity phosphatase 14.
  Acta Crystallogr D Biol Crystallogr, 65, 1013-1020.
PDB code: 2wgp
19818631 M.S.Gentry, J.E.Dixon, and C.A.Worby (2009).
Lafora disease: insights into neurodegeneration from plant metabolism.
  Trends Biochem Sci, 34, 628-639.  
19545434 M.S.Gentry, and R.M.Pace (2009).
Conservation of the glucan phosphatase laforin is linked to rates of molecular evolution and the glucan metabolism of the organism.
  BMC Evol Biol, 9, 138.  
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.  
19888758 S.Wu, S.Vossius, S.Rahmouni, A.V.Miletic, T.Vang, J.Vazquez-Rodriguez, F.Cerignoli, Y.Arimura, S.Williams, T.Hayes, M.Moutschen, S.Vasile, M.Pellecchia, T.Mustelin, and L.Tautz (2009).
Multidentate small-molecule inhibitors of vaccinia H1-related (VHR) phosphatase decrease proliferation of cervix cancer cells.
  J Med Chem, 52, 6716-6723.
PDB code: 3f81
19140798 T.A.Brandão, H.Robinson, S.J.Johnson, and A.C.Hengge (2009).
Impaired acid catalysis by mutation of a protein loop hinge residue in a YopH mutant revealed by crystal structures.
  J Am Chem Soc, 131, 778-786.
PDB codes: 3f99 3f9a 3f9b
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
18236492 H.Park, S.K.Jung, D.G.Jeong, S.E.Ryu, and S.J.Kim (2008).
Discovery of VHR phosphatase inhibitors with micromolar activity based on structure-based virtual screening.
  ChemMedChem, 3, 877-880.  
18573100 R.J.Gruninger, L.Brent Selinger, and S.C.Mosimann (2008).
Effect of ionic strength and oxidation on the P-loop conformation of the protein tyrosine phosphatase-like phytase, PhyAsr.
  FEBS J, 275, 3783-3792.
PDB codes: 2psz 2pt0 3d1h 3d1o 3d1q
17078075 D.G.Jeong, Y.H.Cho, T.S.Yoon, J.H.Kim, S.E.Ryu, and S.J.Kim (2007).
Crystal structure of the catalytic domain of human DUSP5, a dual specificity MAP kinase protein phosphatase.
  Proteins, 66, 253-258.
PDB code: 2g6z
17173287 H.M.Chu, and A.H.Wang (2007).
Enzyme-substrate interactions revealed by the crystal structures of the archaeal Sulfolobus PTP-fold phosphatase and its phosphopeptide complexes.
  Proteins, 66, 996.
PDB codes: 2dxp 2i6i 2i6j 2i6m 2i6o 2i6p
17505108 J.Phan, J.E.Tropea, and D.S.Waugh (2007).
Structure-assisted discovery of Variola major H1 phosphatase inhibitors.
  Acta Crystallogr D Biol Crystallogr, 63, 698-704.
PDB code: 2p4d
17646401 M.S.Gentry, R.H.Dowen, C.A.Worby, S.Mattoo, J.R.Ecker, and J.E.Dixon (2007).
The phosphatase laforin crosses evolutionary boundaries and links carbohydrate metabolism to neuronal disease.
  J Cell Biol, 178, 477-488.  
17115885 P.Chiarugi, and F.Buricchi (2007).
Protein tyrosine phosphorylation and reversible oxidation: two cross-talking posttranslation modifications.
  Antioxid Redox Signal, 9, 1.  
17044055 S.J.Kim, D.G.Jeong, T.S.Yoon, J.H.Son, S.K.Cho, S.E.Ryu, and J.H.Kim (2007).
Crystal structure of human TMDP, a testis-specific dual specificity protein phosphatase: implications for substrate specificity.
  Proteins, 66, 239-245.
PDB code: 2gwo
17427953 S.K.Jung, D.G.Jeong, T.S.Yoon, J.H.Kim, S.E.Ryu, and S.J.Kim (2007).
Crystal structure of human slingshot phosphatase 2.
  Proteins, 68, 408-412.
PDB code: 2nt2
17068812 T.Yokota, Y.Nara, A.Kashima, K.Matsubara, S.Misawa, R.Kato, and S.Sugio (2007).
Crystal structure of human dual specificity phosphatase, JNK stimulatory phosphatase-1, at 1.5 A resolution.
  Proteins, 66, 272-278.
PDB code: 1wrm
17400920 X.Tao, and L.Tong (2007).
Crystal structure of the MAP kinase binding domain and the catalytic domain of human MKP5.
  Protein Sci, 16, 880-886.
PDB codes: 2ouc 2oud
17933004 Z.Shi, S.Tabassum, W.Jiang, J.Zhang, S.Mathur, J.Wu, and Y.Shi (2007).
Identification of a potent inhibitor of human dual-specific phosphatase, VHR, from computer-aided and NMR-based screening to cellular effects.
  Chembiochem, 8, 2092-2099.  
16892390 A.Lavecchia, S.Cosconati, V.Limongelli, and E.Novellino (2006).
Modeling of Cdc25B dual specifity protein phosphatase inhibitors: docking of ligands and enzymatic inhibition mechanism.
  ChemMedChem, 1, 540-550.  
16699184 D.G.Jeong, Y.H.Cho, T.S.Yoon, J.H.Kim, J.H.Son, S.E.Ryu, and S.J.Kim (2006).
Structure of human DSP18, a member of the dual-specificity protein tyrosine phosphatase family.
  Acta Crystallogr D Biol Crystallogr, 62, 582-588.
PDB code: 2esb
16452434 H.Xu, B.Xia, and C.Jin (2006).
Solution structure of a low-molecular-weight protein tyrosine phosphatase from Bacillus subtilis.
  J Bacteriol, 188, 1509-1517.
PDB code: 1zgg
16410353 M.J.Begley, G.S.Taylor, M.A.Brock, P.Ghosh, V.L.Woods, and J.E.Dixon (2006).
Molecular basis for substrate recognition by MTMR2, a myotubularin family phosphoinositide phosphatase.
  Proc Natl Acad Sci U S A, 103, 927-932.
PDB codes: 1zsq 1zvr
16413071 R.Merritt, M.J.Hayman, and Y.M.Agazie (2006).
Mutation of Thr466 in SHP2 abolishes its phosphatase activity, but provides a new substrate-trapping mutant.
  Biochim Biophys Acta, 1763, 45-56.  
16845380 T.H.Kang, and K.T.Kim (2006).
Negative regulation of ERK activity by VRK3-mediated activation of VHR phosphatase.
  Nat Cell Biol, 8, 863-869.  
15822194 A.P.Ducruet, A.Vogt, P.Wipf, and J.S.Lazo (2005).
Dual specificity protein phosphatases: therapeutic targets for cancer and Alzheimer's disease.
  Annu Rev Pharmacol Toxicol, 45, 725-750.  
15743966 C.Madhurantakam, E.Rajakumara, P.A.Mazumdar, B.Saha, D.Mitra, H.G.Wiker, R.Sankaranarayanan, and A.K.Das (2005).
Crystal structure of low-molecular-weight protein tyrosine phosphatase from Mycobacterium tuberculosis at 1.9-A resolution.
  J Bacteriol, 187, 2175-2181.
PDB codes: 1u2p 1u2q
15670209 K.Hamada, M.Kato, T.Shimizu, K.Ihara, T.Mizuno, and T.Hakoshima (2005).
Crystal structure of the protein histidine phosphatase SixA in the multistep His-Asp phosphorelay.
  Genes Cells, 10, 1.
PDB codes: 1ujb 1ujc
15900534 L.Bialy, and H.Waldmann (2005).
Inhibitors of protein tyrosine phosphatases: next-generation drugs?
  Angew Chem Int Ed Engl, 44, 3814-3839.  
15930137 M.S.Gentry, C.A.Worby, and J.E.Dixon (2005).
Insights into Lafora disease: malin is an E3 ubiquitin ligase that ubiquitinates and promotes the degradation of laforin.
  Proc Natl Acad Sci U S A, 102, 8501-8506.  
16170801 T.S.Yoon, D.G.Jeong, J.H.Kim, Y.H.Cho, J.H.Son, J.W.Lee, S.E.Ryu, and S.J.Kim (2005).
Crystal structure of the catalytic domain of human VHY, a dual-specificity protein phosphatase.
  Proteins, 61, 694-697.
PDB code: 1yz4
14997562 A.Bhaduri, R.Ravishankar, and R.Sowdhamini (2004).
Conserved spatially interacting motifs of protein superfamilies: application to fold recognition and function annotation of genome data.
  Proteins, 54, 657-670.  
15390114 N.Muja, G.Lovas, E.Romm, D.Machleder, M.Ranjan, V.Gallo, and L.D.Hudson (2004).
Expression of a catalytically inactive transmembrane protein tyrosine phosphatase epsilon (tm-PTP epsilon) delays optic nerve myelination.
  Glia, 48, 278-297.  
12853468 C.H.Gray, V.M.Good, N.K.Tonks, and D.Barford (2003).
The structure of the cell cycle protein Cdc14 reveals a proline-directed protein phosphatase.
  EMBO J, 22, 3524-3535.
PDB codes: 1ohc 1ohd 1ohe
12795696 E.P.Risseeuw, T.E.Daskalchuk, T.W.Banks, E.Liu, J.Cotelesage, H.Hellmann, M.Estelle, D.E.Somers, and W.L.Crosby (2003).
Protein interaction analysis of SCF ubiquitin E3 ligase subunits from Arabidopsis.
  Plant J, 34, 753-767.  
14690594 M.J.Begley, G.S.Taylor, S.A.Kim, D.M.Veine, J.E.Dixon, and J.A.Stuckey (2003).
Crystal structure of a phosphoinositide phosphatase, MTMR2: insights into myotubular myopathy and Charcot-Marie-Tooth syndrome.
  Mol Cell, 12, 1391-1402.
PDB codes: 1lw3 1m7r
14690430 Y.Kim, A.E.Rice, and J.M.Denu (2003).
Intramolecular dephosphorylation of ERK by MKP3.
  Biochemistry, 42, 15197-15207.  
  12184814 A.Theodosiou, and A.Ashworth (2002).
MAP kinase phosphatases.
  Genome Biol, 3, REVIEWS3009.  
12186556 H.Fu, J.Park, and D.Pei (2002).
Peptidyl aldehydes as reversible covalent inhibitors of protein tyrosine phosphatases.
  Biochemistry, 41, 10700-10709.  
12461518 M.A.Lyon, A.P.Ducruet, P.Wipf, and J.S.Lazo (2002).
Dual-specificity phosphatases as targets for antineoplastic agents.
  Nat Rev Drug Discov, 1, 961-976.  
11863439 M.A.Schumacher, J.L.Todd, A.E.Rice, K.G.Tanner, and J.M.Denu (2002).
Structural basis for the recognition of a bisphosphorylated MAP kinase peptide by human VHR protein Phosphatase.
  Biochemistry, 41, 3009-3017.
PDB code: 1j4x
11782565 T.P.Shanley (2002).
Phosphatases: counterregulatory role in inflammatory cell signaling.
  Crit Care Med, 30, S80-S88.  
11807171 Z.Y.Zhang (2002).
Protein tyrosine phosphatases: structure and function, substrate specificity, and inhibitor development.
  Annu Rev Pharmacol Toxicol, 42, 209-234.  
12191622 Z.Y.Zhang, B.Zhou, and L.Xie (2002).
Modulation of protein kinase signaling by protein phosphatases and inhibitors.
  Pharmacol Ther, 93, 307-317.  
11350947 A.Changela, C.K.Ho, A.Martins, S.Shuman, and A.Mondragón (2001).
Structure and mechanism of the RNA triphosphatase component of mammalian mRNA capping enzyme.
  EMBO J, 20, 2575-2586.
PDB codes: 1i9s 1i9t
11463386 H.Song, N.Hanlon, N.R.Brown, M.E.Noble, L.N.Johnson, and D.Barford (2001).
Phosphoprotein-protein interactions revealed by the crystal structure of kinase-associated phosphatase in complex with phosphoCDK2.
  Mol Cell, 7, 615-626.
PDB codes: 1fpz 1fq1
11248552 N.K.Tonks, and B.G.Neel (2001).
Combinatorial control of the specificity of protein tyrosine phosphatases.
  Curr Opin Cell Biol, 13, 182-195.  
11755399 T.Usui, S.Kojima, S.Kidokoro, K.Ueda, H.Osada, and M.Sodeoka (2001).
Design and synthesis of a dimeric derivative of RK-682 with increased inhibitory activity against VHR, a dual-specificity ERK phosphatase: implications for the molecular mechanism of the inhibition.
  Chem Biol, 8, 1209-1220.  
11717427 Y.Shen, R.Luche, B.Wei, M.L.Gordon, C.D.Diltz, and N.K.Tonks (2001).
Activation of the Jnk signaling pathway by a dual-specificity phosphatase, JSP-1.
  Proc Natl Acad Sci U S A, 98, 13613-13618.  
10723800 L.Li, and J.E.Dixon (2000).
Form, function, and regulation of protein tyrosine phosphatases and their involvement in human diseases.
  Semin Immunol, 12, 75-84.  
10712927 S.M.Keyse (2000).
Protein phosphatases and the regulation of mitogen-activated protein kinase signalling.
  Curr Opin Cell Biol, 12, 186-192.  
10388775 G.H.Peters, T.M.Frimurer, J.N.Andersen, and O.H.Olsen (1999).
Molecular dynamics simulations of protein-tyrosine phosphatase 1B. I. ligand-induced changes in the protein motions.
  Biophys J, 77, 505-515.  
10555148 J.O.Lee, H.Yang, M.M.Georgescu, A.Di Cristofano, T.Maehama, Y.Shi, J.E.Dixon, P.Pandolfi, and N.P.Pavletich (1999).
Crystal structure of the PTEN tumor suppressor: implications for its phosphoinositide phosphatase activity and membrane association.
  Cell, 99, 323-334.
PDB code: 1d5r
10409830 K.Kolmodin, P.Nordlund, and J.Aqvist (1999).
Mechanism of substrate dephosphorylation in low Mr protein tyrosine phosphatase.
  Proteins, 36, 370-379.  
9646865 D.Barford, A.K.Das, and M.P.Egloff (1998).
The structure and mechanism of protein phosphatases: insights into catalysis and regulation.
  Annu Rev Biophys Biomol Struct, 27, 133-164.  
9689104 I.De Vivo, X.Cui, J.Domen, and M.L.Cleary (1998).
Growth stimulation of primary B cell precursors by the anti-phosphatase Sbf1.
  Proc Natl Acad Sci U S A, 95, 9471-9476.  
9818190 J.M.Denu, and J.E.Dixon (1998).
Protein tyrosine phosphatases: mechanisms of catalysis and regulation.
  Curr Opin Chem Biol, 2, 633-641.  
9757831 M.J.Wishart, and J.E.Dixon (1998).
Gathering STYX: phosphatase-like form predicts functions for unique protein-interaction domains.
  Trends Biochem Sci, 23, 301-306.  
9817026 T.R.Burke, and Z.Y.Zhang (1998).
Protein-tyrosine phosphatases: structure, mechanism, and inhibitor discovery.
  Biopolymers, 47, 225-241.  
9537414 X.Cui, I.De Vivo, R.Slany, A.Miyamoto, R.Firestein, and M.L.Cleary (1998).
Association of SET domain and myotubularin-related proteins modulates growth control.
  Nat Genet, 18, 331-337.  
9356475 F.B.Furnari, H.Lin, H.S.Huang, and W.K.Cavenee (1997).
Growth suppression of glioma cells by PTEN requires a functional phosphatase catalytic domain.
  Proc Natl Acad Sci U S A, 94, 12479-12484.  
9141461 G.Draetta, and J.Eckstein (1997).
Cdc25 protein phosphatases in cell proliferation.
  Biochim Biophys Acta, 1332, M53-M63.  
9256433 M.P.Myers, J.P.Stolarov, C.Eng, J.Li, S.I.Wang, M.H.Wigler, R.Parsons, and N.K.Tonks (1997).
P-TEN, the tumor suppressor from human chromosome 10q23, is a dual-specificity phosphatase.
  Proc Natl Acad Sci U S A, 94, 9052-9057.  
9399917 M.P.Myers, and N.K.Tonks (1997).
PTEN: sometimes taking it off can be better than putting it on.
  Am J Hum Genet, 61, 1234-1238.  
  8976573 D.T.Haynie, and C.P.Ponting (1996).
The N-terminal domains of tensin and auxilin are phosphatase homologues.
  Protein Sci, 5, 2643-2646.  
8987394 E.B.Fauman, and M.A.Saper (1996).
Structure and function of the protein tyrosine phosphatases.
  Trends Biochem Sci, 21, 413-417.  
8898189 J.M.Denu, J.A.Stuckey, M.A.Saper, and J.E.Dixon (1996).
Form and function in protein dephosphorylation.
  Cell, 87, 361-364.  
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 code is shown on the right.

 

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