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PDBsum entry 1mkp

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Hydrolase PDB id
1mkp
Jmol
Contents
Protein chain
144 a.a. *
Ligands
MPD
Metals
_CL
Waters ×40
* Residue conservation analysis
PDB id:
1mkp
Name: Hydrolase
Title: Crystal structure of pyst1 (mkp3)
Structure: Pyst1. Chain: a. Fragment: catalytic domain. Synonym: dual specificity phosphatase, map kinase phosphatase 3, mkp-3. Engineered: yes. Mutation: yes. Other_details: mpd and chloride ion
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
Resolution:
2.35Å     R-factor:   0.201     R-free:   0.235
Authors: A.E.Stewart,S.Dowd,S.Keyse,N.Q.Mcdonald
Key ref:
A.E.Stewart et al. (1999). Crystal structure of the MAPK phosphatase Pyst1 catalytic domain and implications for regulated activation. Nat Struct Biol, 6, 174-181. PubMed id: 10048930 DOI: 10.1038/5861
Date:
11-Jul-98     Release date:   22-Jul-99    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q16828  (DUS6_HUMAN) -  Dual specificity protein phosphatase 6
Seq:
Struc:
381 a.a.
144 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 2 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class 1: E.C.3.1.3.16  - Protein-serine/threonine phosphatase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: [a protein]-serine/threonine phosphate + H2O = [a protein]- serine/threonine + phosphate
[a protein]-serine/threonine phosphate
+ H(2)O
= [a protein]- serine/threonine
+ phosphate
   Enzyme class 2: E.C.3.1.3.48  - Protein-tyrosine-phosphatase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Protein tyrosine phosphate + H2O = protein tyrosine + phosphate
Protein tyrosine phosphate
+ H(2)O
= protein tyrosine
+ 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
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     dephosphorylation   2 terms 
  Biochemical function     phosphatase activity     3 terms  

 

 
    reference    
 
 
DOI no: 10.1038/5861 Nat Struct Biol 6:174-181 (1999)
PubMed id: 10048930  
 
 
Crystal structure of the MAPK phosphatase Pyst1 catalytic domain and implications for regulated activation.
A.E.Stewart, S.Dowd, S.M.Keyse, N.Q.McDonald.
 
  ABSTRACT  
 
The crystal structure of the catalytic domain from the MAPK phosphatase Pyst1 (Pyst1-CD) has been determined at 2.35 A. The structure adopts a protein tyrosine phosphatase (PTPase) fold with a shallow active site that displays a distorted geometry in the absence of its substrate with some similarity to the dual-specificity phosphatase cdc25. Functional characterization of Pyst1-CD indicates it is sufficient to dephosphorylate activated ERK2 in vitro. Kinetic analysis of Pyst1 and Pyst1-CD using the substrate p-nitrophenyl phosphate (pNPP) reveals that both molecules undergo catalytic activation in the presence of recombinant inactive ERK2, switching from a low- to high-activity form. Mutation of Asp 262, located 5.5 A distal to the active site, demonstrates it is essential for catalysis in the high-activity ERK2-dependent conformation of Pyst1 but not for the low-activity ERK2-independent form, suggesting that ERK2 induces closure of the Asp 262 loop over the active site, thereby enhancing Pyst1 catalytic efficiency.
 
  Selected figure(s)  
 
Figure 3.
Figure 3. The chloride ion is shown as a cyan sphere, oxygen atoms of water molecules as red spheres and Trp 264 of a symmetry−related molecule is drawn in purple. b, Superposition of the PTP−loop, putative general acid loop and variable insert sequence of Pyst1−CD (standard element colors) with equivalent regions from VHR (green). Selected side chains for Pyst1−CD and VHR are shown and the Pyst1−CD side chains are labeled. Hydrogen bonds between the phosphate−binding Arg 130 of VHR and the carbonyl oxygen from residues 69 and 90 are shown. The chloride ion of Pyst1−CD is omitted for clarity. c, Superposition of the same regions and side chains of Pyst1−CD with PTP1B (purple). Arg 221 of PTP1B contacts Glu 115 and the carbonyl oxygen of residues 110 and 179. d, Superposition of equivalent regions of cdc25a with Pyst1−CD, highlighting Cys 430, Glu 431 and Arg 436 of cdc25a. Although the active sites of these phosphatases are similar, their topological folds are quite different^[297]5.The two structures have an r.m.s. difference of 1.89 Å for 55 C [298]alpha atoms This figure was prepared using SETOR^[299]32.
Figure 6.
Figure 6. A hypothetical model for the interaction of Pyst1 with ERK2. The structure of Pyst1−CD (green) was superposed onto the coordinates of PTP1B (PDB accession code 1PTV). Residue Tyr 185 of activated ERK2 was superposed onto a phospho−tyrosine substrate within the active site of PTP1B. This transformation was then applied to the entire coordinate set of activated ERK2 (PDB accession code 2ERK). Phosphorylated residues Thr 183 and Tyr 185 in addition to Asp 319 are highlighted on the ERK2 backbone (cyan). Mutation of Asp 319 to Asn in the Drosophila Sevenmaker MAPK leads to a MAPK that is resistant to and unable to interact with Pyst1 (10). We have made the assumption that Pyst1−ND makes contacts to Asp 319, and it is this interaction that is perturbed by the Sevenmaker mutant. A model for the Pyst1 amino−terminal domain (Pyst1−ND), based on cdc25 structure (PDB accession code 1CD25), is also shown in red, positioning the noncatalytic active site of Pyst1−ND to contact Asp 319. The connecting loop (residues 148−203) between the Pyst1−ND and Pyst1−CD domains is represented by white dots.
 
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Struct Biol (1999, 6, 174-181) copyright 1999.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference Google scholar

  PubMed id Reference
20224945 J.Pytela, T.Kato, and T.Hashimoto (2010).
Mitogen-activated protein kinase phosphatase PHS1 is retained in the cytoplasm by nuclear extrusion signal-dependent and independent mechanisms.
  Planta, 231, 1311-1322.  
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
19578332 G.Molina, A.Vogt, A.Bakan, W.Dai, P.Queiroz de Oliveira, W.Znosko, T.E.Smithgall, I.Bahar, J.S.Lazo, B.W.Day, and M.Tsang (2009).
Zebrafish chemical screening reveals an inhibitor of Dusp6 that expands cardiac cell lineages.
  Nat Chem Biol, 5, 680-687.  
  19436832 L.Li, S.F.Chen, and Y.Liu (2009).
MAP kinase phosphatase-1, a critical negative regulator of the innate immune response.
  Int J Clin Exp Med, 2, 48-67.  
18855677 A.Bakan, J.S.Lazo, P.Wipf, K.M.Brummond, and I.Bahar (2008).
Toward a molecular understanding of the interaction of dual specificity phosphatases with substrates: insights from structure-based modeling and high throughput screening.
  Curr Med Chem, 15, 2536-2544.  
18554149 J.A.Ralph, and E.F.Morand (2008).
MAPK phosphatases as novel targets for rheumatoid arthritis.
  Expert Opin Ther Targets, 12, 795-808.  
18694935 J.K.Mark, R.A.Aubin, S.Smith, and M.A.Hefford (2008).
Inhibition of Mitogen-activated Protein Kinase Phosphatase 3 Activity by Interdomain Binding.
  J Biol Chem, 283, 28574-28583.  
18579522 K.Lee, E.H.Song, H.S.Kim, J.H.Yoo, H.J.Han, M.S.Jung, S.M.Lee, K.E.Kim, M.C.Kim, M.J.Cho, and W.S.Chung (2008).
Regulation of MAPK Phosphatase 1 (AtMKP1) by Calmodulin in Arabidopsis.
  J Biol Chem, 283, 23581-23588.  
18321244 M.Ekerot, M.P.Stavridis, L.Delavaine, M.P.Mitchell, C.Staples, D.M.Owens, I.D.Keenan, R.J.Dickinson, K.G.Storey, and S.M.Keyse (2008).
Negative-feedback regulation of FGF signalling by DUSP6/MKP-3 is driven by ERK1/2 and mediated by Ets factor binding to a conserved site within the DUSP6/MKP-3 gene promoter.
  Biochem J, 412, 287-298.  
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
18809681 S.Kurita, Y.Watanabe, E.Gunji, K.Ohashi, and K.Mizuno (2008).
Molecular Dissection of the Mechanisms of Substrate Recognition and F-actin-mediated Activation of Cofilin-phosphatase Slingshot-1.
  J Biol Chem, 283, 32542-32552.  
17596826 A.K.Nordle, P.Rios, A.Gaulton, R.Pulido, T.K.Attwood, and L.Tabernero (2007).
Functional assignment of MAPK phosphatase domains.
  Proteins, 69, 19-31.  
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
17313454 D.M.Arnold, C.Foster, D.M.Huryn, J.S.Lazo, P.A.Johnston, and P.Wipf (2007).
Synthesis and biological activity of a focused library of mitogen-activated protein kinase phosphatase inhibitors.
  Chem Biol Drug Des, 69, 23-30.  
17496916 D.M.Owens, and S.M.Keyse (2007).
Differential regulation of MAP kinase signalling by dual-specificity protein phosphatases.
  Oncogene, 26, 3203-3213.  
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
17512700 X.Wang, and Y.Liu (2007).
Regulation of innate immune response by MAP kinase phosphatase-1.
  Cell Signal, 19, 1372-1382.  
17046812 B.Zhou, J.Zhang, S.Liu, S.Reddy, F.Wang, and Z.Y.Zhang (2006).
Mapping ERK2-MKP3 binding interfaces by hydrogen/deuterium exchange mass spectrometry.
  J Biol Chem, 281, 38834-38844.  
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
15753082 A.Vogt, A.Tamewitz, J.Skoko, R.P.Sikorski, K.A.Giuliano, and J.S.Lazo (2005).
The benzo[c]phenanthridine alkaloid, sanguinarine, is a selective, cell-active inhibitor of mitogen-activated protein kinase phosphatase-1.
  J Biol Chem, 280, 19078-19086.  
16135819 G.R.Christie, D.J.Williams, F.Macisaac, R.J.Dickinson, I.Rosewell, and S.M.Keyse (2005).
The dual-specificity protein phosphatase DUSP9/MKP-4 is essential for placental function but is not required for normal embryonic development.
  Mol Cell Biol, 25, 8323-8333.  
15899879 J.J.Wu, L.Zhang, and A.M.Bennett (2005).
The noncatalytic amino terminus of mitogen-activated protein kinase phosphatase 1 directs nuclear targeting and serum response element transcriptional regulation.
  Mol Cell Biol, 25, 4792-4803.  
15713638 M.Mandl, D.N.Slack, and S.M.Keyse (2005).
Specific inactivation and nuclear anchoring of extracellular signal-regulated kinase 2 by the inducible dual-specificity protein phosphatase DUSP5.
  Mol Cell Biol, 25, 1830-1845.  
15632084 S.Marchetti, C.Gimond, J.C.Chambard, T.Touboul, D.Roux, J.Pouysségur, and G.Pagès (2005).
Extracellular signal-regulated kinases phosphorylate mitogen-activated protein kinase phosphatase 3/DUSP6 at serines 159 and 197, two sites critical for its proteasomal degradation.
  Mol Cell Biol, 25, 854-864.  
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
15201283 A.Alonso, S.Burkhalter, J.Sasin, L.Tautz, J.Bogetz, H.Huynh, M.C.Bremer, L.J.Holsinger, A.Godzik, and T.Mustelin (2004).
The minimal essential core of a cysteine-based protein-tyrosine phosphatase revealed by a novel 16-kDa VH1-like phosphatase, VHZ.
  J Biol Chem, 279, 35768-35774.  
15096509 A.Kar-Roy, H.Korkaya, R.Oberoi, S.K.Lal, and S.Jameel (2004).
The hepatitis E virus open reading frame 3 protein activates ERK through binding and inhibition of the MAPK phosphatase.
  J Biol Chem, 279, 28345-28357.  
14704153 G.Kozlov, J.Cheng, E.Ziomek, D.Banville, K.Gehring, and I.Ekiel (2004).
Structural insights into molecular function of the metastasis-associated phosphatase PRL-3.
  J Biol Chem, 279, 11882-11889.
PDB code: 1r6h
15269220 M.Karlsson, J.Mathers, R.J.Dickinson, M.Mandl, and S.M.Keyse (2004).
Both nuclear-cytoplasmic shuttling of the dual specificity phosphatase MKP-3 and its ability to anchor MAP kinase in the cytoplasm are mediated by a conserved nuclear export signal.
  J Biol Chem, 279, 41882-41891.  
12954332 A.Vogt, K.A.Cooley, M.Brisson, M.G.Tarpley, P.Wipf, and J.S.Lazo (2003).
Cell-active dual specificity phosphatase inhibitors identified by high-content screening.
  Chem Biol, 10, 733-742.  
12754209 J.Zhang, B.Zhou, C.F.Zheng, and Z.Y.Zhang (2003).
A bipartite mechanism for ERK2 recognition by its cognate regulators and substrates.
  J Biol Chem, 278, 29901-29912.  
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.  
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.  
11239467 A.Farooq, G.Chaturvedi, S.Mujtaba, O.Plotnikova, L.Zeng, C.Dhalluin, R.Ashton, and M.M.Zhou (2001).
Solution structure of ERK2 binding domain of MAPK phosphatase MKP-3: structural insights into MKP-3 activation by ERK2.
  Mol Cell, 7, 387-399.
PDB code: 1hzm
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
11284696 J.D.Rigas, R.H.Hoff, A.E.Rice, A.C.Hengge, and J.M.Denu (2001).
Transition state analysis and requirement of Asp-262 general acid/base catalyst for full activation of dual-specificity phosphatase MKP3 by extracellular regulated kinase.
  Biochemistry, 40, 4398-4406.  
11591707 T.Zhang, M.W.Wolfe, and M.S.Roberson (2001).
An early growth response protein (Egr) 1 cis-element is required for gonadotropin-releasing hormone-induced mitogen-activated protein kinase phosphatase 2 gene expression.
  J Biol Chem, 276, 45604-45613.  
10911997 B.O.Krogh, and S.Shuman (2000).
Catalytic mechanism of DNA topoisomerase IB.
  Mol Cell, 5, 1035-1041.  
10702230 C.C.Fjeld, A.E.Rice, Y.Kim, K.R.Gee, and J.M.Denu (2000).
Mechanistic basis for catalytic activation of mitogen-activated protein kinase phosphatase 3 by extracellular signal-regulated kinase.
  J Biol Chem, 275, 6749-6757.  
10712927 S.M.Keyse (2000).
Protein phosphatases and the regulation of mitogen-activated protein kinase signalling.
  Curr Opin Cell Biol, 12, 186-192.  
10675316 S.Zolnierowicz, and M.Bollen (2000).
Protein phosphorylation and protein phosphatases. De Panne, Belgium, September 19-24, 1999.
  EMBO J, 19, 483-488.  
10585426 B.Zhou, and Z.Y.Zhang (1999).
Mechanism of mitogen-activated protein kinase phosphatase-3 activation by ERK2.
  J Biol Chem, 274, 35526-35534.  
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.