PDBsum entry 1hzm

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protein links
Hydrolase PDB id
Protein chain
154 a.a. *
* Residue conservation analysis
PDB id:
Name: Hydrolase
Title: Structure of erk2 binding domain of mapk phosphatase mkp-3: structural insights into mkp-3 activation by erk2
Structure: Dual specificity protein phosphatase 6. Chain: a. Fragment: residues 1-154. Synonym: mitogen-activated protein kinase phosphatase 3. Map kinase phosphatase 3. Mkp-3. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
NMR struc: 1 models
Authors: A.Farooq,M.-M.Zhou
Key ref:
A.Farooq et al. (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. PubMed id: 11239467 DOI: 10.1016/S1097-2765(01)00186-1
25-Jan-01     Release date:   25-Jan-02    
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Protein chain
Pfam   ArchSchema ?
Q16828  (DUS6_HUMAN) -  Dual specificity protein phosphatase 6
381 a.a.
154 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class 1: E.C.  - 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.  - 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


DOI no: 10.1016/S1097-2765(01)00186-1 Mol Cell 7:387-399 (2001)
PubMed id: 11239467  
Solution structure of ERK2 binding domain of MAPK phosphatase MKP-3: structural insights into MKP-3 activation by ERK2.
A.Farooq, G.Chaturvedi, S.Mujtaba, O.Plotnikova, L.Zeng, C.Dhalluin, R.Ashton, M.M.Zhou.
MAP kinases (MAPKs), which control mitogenic signal transduction in all eukaryotic organisms, are inactivated by dual specificity MAPK phosphatases (MKPs). MKP-3, a prototypical MKP, achieves substrate specificity through its N-terminal domain binding to the MAPK ERK2, resulting in the activation of its C-terminal phosphatase domain. The solution structure and biochemical analysis of the ERK2 binding (EB) domain of MKP-3 show that regions that are essential for ERK2 binding partly overlap with its sites that interact with the C-terminal catalytic domain, and that these interactions are functionally coupled to the active site residues of MKP-3. Our findings suggest a novel mechanism by which the EB domain binding to ERK2 is transduced to cause a conformational change of the C-terminal catalytic domain, resulting in the enzymatic activation of MKP-3.
  Selected figure(s)  
Figure 2.
Figure 2. Overview of the MKP-3 EB Domain Structure(A) Stereoview of the backbone atoms (N, C^α, and C′) of 20 superimposed NMR-derived structures of the MKP-3 EB domain (residues 10–152). The terminal residues, which are structurally disordered, are omitted for clarity. The secondary structural elements of α helices and β strands are colored in green and orange, respectively. These figures were produced using InsightII.(B) Ribbon depiction of the averaged minimized NMR structure of the EB domain. The orientation of the protein structure in (B) is as shown in (A). The color-coding scheme for α helices and β strands is the same as that used in (A).(C) Ribbon diagram of the EB domain structure, rotated vert, similar 90° from the orientation in (B) as indicated in the figure. These figures were prepared using Ribbons (Carson, 1991)
Figure 5.
Figure 5. Electrostatic Potential Surface Representations of the MKP-3 EB Domain and ERK2(A) Electrostatic potential map of the MKP-3 EB domain. Negatively and positively charged residues are shown in red and blue, respectively. Orientation of the molecular surface representation is shown in Figure 3C, rotated clockwise by vert, similar 60° about the vertical axis. Numerals indicate specific amino acid residues of the protein.(B) Electrostatic potential map of ERK2. Negatively and positively charged residues are shown in red and blue, respectively. Numerals indicate locations of functionally important amino acid residues of the protein, including D319 as well as T183 and Y185 in the activation loop
  The above figures are reprinted by permission from Cell Press: Mol Cell (2001, 7, 387-399) copyright 2001.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20005866 C.B.McDonald, K.L.Seldeen, B.J.Deegan, V.Bhat, and A.Farooq (2010).
Assembly of the Sos1-Grb2-Gab1 ternary signaling complex is under allosteric control.
  Arch Biochem Biophys, 494, 216-225.  
20622857 G.J.Bartlett, A.Choudhary, R.T.Raines, and D.N.Woolfson (2010).
n-->pi* interactions in proteins.
  Nat Chem Biol, 6, 615-620.  
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.  
18644985 D.J.Morrison, M.K.Kim, W.Berkofsky-Fessler, and J.D.Licht (2008).
WT1 induction of mitogen-activated protein kinase phosphatase 3 represents a novel mechanism of growth suppression.
  Mol Cancer Res, 6, 1225-1231.  
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.  
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.  
17496916 D.M.Owens, and S.M.Keyse (2007).
Differential regulation of MAP kinase signalling by dual-specificity protein phosphatases.
  Oncogene, 26, 3203-3213.  
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
17473844 K.L.Jeffrey, M.Camps, C.Rommel, and C.R.Mackay (2007).
Targeting dual-specificity phosphatases: manipulating MAP kinase signalling and immune responses.
  Nat Rev Drug Discov, 6, 391-403.  
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
18060821 Y.Zhu, H.Li, C.Long, L.Hu, H.Xu, L.Liu, S.Chen, D.C.Wang, and F.Shao (2007).
Structural insights into the enzymatic mechanism of the pathogenic MAPK phosphothreonine lyase.
  Mol Cell, 28, 899-913.
PDB codes: 2p1w 2q8y
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.  
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.  
16148006 C.Tárrega, P.Ríos, R.Cejudo-Marín, C.Blanco-Aparicio, L.van den Berk, J.Schepens, W.Hendriks, L.Tabernero, and R.Pulido (2005).
ERK2 shows a restrictive and locally selective mechanism of recognition by its tyrosine phosphatase inactivators not shared by its activator MEK1.
  J Biol Chem, 280, 37885-37894.  
15576557 D.Pantoja-Uceda, B.López-Méndez, S.Koshiba, M.Inoue, T.Kigawa, T.Terada, M.Shirouzu, A.Tanaka, M.Seki, K.Shinozaki, S.Yokoyama, and P.Güntert (2005).
Solution structure of the rhodanese homology domain At4g01050(175-295) from Arabidopsis thaliana.
  Protein Sci, 14, 224-230.
PDB code: 1vee
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.  
15590690 J.S.Lee, J.J.Lee, and J.S.Seo (2005).
HSP70 deficiency results in activation of c-Jun N-terminal Kinase, extracellular signal-regulated kinase, and caspase-3 in hyperosmolarity-induced apoptosis.
  J Biol Chem, 280, 6634-6641.  
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.  
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.  
15252030 H.H.Chen, R.Luche, B.Wei, and N.K.Tonks (2004).
Characterization of two distinct dual specificity phosphatases encoded in alternative open reading frames of a single gene located on human chromosome 10q22.2.
  J Biol Chem, 279, 41404-41413.  
15284227 M.Castelli, M.Camps, C.Gillieron, D.Leroy, S.Arkinstall, C.Rommel, and A.Nichols (2004).
MAP kinase phosphatase 3 (MKP3) interacts with and is phosphorylated by protein kinase CK2alpha.
  J Biol Chem, 279, 44731-44739.  
14701731 M.Kim, G.H.Cha, S.Kim, J.H.Lee, J.Park, H.Koh, K.Y.Choi, and J.Chung (2004).
MKP-3 has essential roles as a negative regulator of the Ras/mitogen-activated protein kinase pathway during Drosophila development.
  Mol Cell Biol, 24, 573-583.  
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.  
12794087 K.Masuda, H.Shima, C.Katagiri, and K.Kikuchi (2003).
Activation of ERK induces phosphorylation of MAPK phosphatase-7, a JNK specific phosphatase, at Ser-446.
  J Biol Chem, 278, 32448-32456.  
  12759238 T.Furukawa, M.Sunamura, F.Motoi, S.Matsuno, and A.Horii (2003).
Potential tumor suppressive pathway involving DUSP6/MKP-3 in pancreatic cancer.
  Am J Pathol, 162, 1807-1815.  
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.  
11782450 J.J.Seidel, and B.J.Graves (2002).
An ERK2 docking site in the Pointed domain distinguishes a subset of ETS transcription factors.
  Genes Dev, 16, 127-137.  
11953434 T.Tanoue, T.Yamamoto, and E.Nishida (2002).
Modular structure of a docking surface on MAPK phosphatases.
  J Biol Chem, 277, 22942-22949.  
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.