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PDBsum entry 2cfv

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protein metals links
Hydrolase PDB id
2cfv
Jmol
Contents
Protein chain
268 a.a. *
Metals
_NI ×4
_CL
Waters ×25
* Residue conservation analysis
PDB id:
2cfv
Name: Hydrolase
Title: Crystal structure of human protein tyrosine phosphatase receptor type j
Structure: Human protein tyrosine phosphatase receptor type chain: a. Fragment: residues 1019-1311. Synonym: protein-tyrosine phosphatase eta, r-ptp-eta, hptp protein-tyrosine phosphatase receptor type j, density-enha phosphatase 1, dep-1, cd14 8 antigen. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 469008.
Biol. unit: Trimer (from PDB file)
Resolution:
2.50Å     R-factor:   0.203     R-free:   0.250
Authors: J.E.Debreczeni,A.J.Barr,J.Eswaran,E.Ugochukwu,M.Sundstrom,J. C.Arrowsmith,A.Edwards,S.Knapp
Key ref:
A.J.Barr et al. (2009). Large-scale structural analysis of the classical human protein tyrosine phosphatome. Cell, 136, 352-363. PubMed id: 19167335 DOI: 10.1016/j.cell.2008.11.038
Date:
23-Feb-06     Release date:   09-Mar-06    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q12913  (PTPRJ_HUMAN) -  Receptor-type tyrosine-protein phosphatase eta
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
1337 a.a.
268 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 20 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: 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
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     2 terms  

 

 
    reference    
 
 
DOI no: 10.1016/j.cell.2008.11.038 Cell 136:352-363 (2009)
PubMed id: 19167335  
 
 
Large-scale structural analysis of the classical human protein tyrosine phosphatome.
A.J.Barr, E.Ugochukwu, W.H.Lee, O.N.King, P.Filippakopoulos, I.Alfano, P.Savitsky, N.A.Burgess-Brown, S.Müller, S.Knapp.
 
  ABSTRACT  
 
Protein tyrosine phosphatases (PTPs) play a critical role in regulating cellular functions by selectively dephosphorylating their substrates. Here we present 22 human PTP crystal structures that, together with prior structural knowledge, enable a comprehensive analysis of the classical PTP family. Despite their largely conserved fold, surface properties of PTPs are strikingly diverse. A potential secondary substrate-binding pocket is frequently found in phosphatases, and this has implications for both substrate recognition and development of selective inhibitors. Structural comparison identified four diverse catalytic loop (WPD) conformations and suggested a mechanism for loop closure. Enzymatic assays revealed vast differences in PTP catalytic activity and identified PTPD1, PTPD2, and HDPTP as catalytically inert protein phosphatases. We propose a "head-to-toe" dimerization model for RPTPgamma/zeta that is distinct from the "inhibitory wedge" model and that provides a molecular basis for inhibitory regulation. This phosphatome resource gives an expanded insight into intrafamily PTP diversity, catalytic activity, substrate recognition, and autoregulatory self-association.
 
  Selected figure(s)  
 
Figure 3.
Figure 3. Novel Conformations and Movement of the Catalytic (WPD) Loop
(A) WPD loop conformations are shown by a PTP representative of each state: closed (blue, PTP1B, PDB: 1SUG); open (yellow, PTP1B, PDB: 2HNP); and atypical (magenta, GLEPP1, PDB: 2GJT; STEP, PDB: 2BIJ; Lyp, PDB: 2P6X). The intermediate WPD loop conformation of PCPTP1 (PDB: 2A8B) is not shown for clarity. Other PTP structures are shown with a thin transparent line tracing the backbone and are colored according to conformation.
(B) Superimposition of the structure of STEP-C/S in complex with pY (PDB: 2CJZ; gray) and the apo STEP (PDB: 2BIJ; light green) showing that the WPD loop conformation does not change on substrate binding (pTyr, orange). The catalytic water molecule (Wa) corresponding to that found in closed structures is shown.
(C) Superimposition of the structure of STEP-C/S in complex with pY (PDB: 2CJZ; green) and PTP1B with the insulin receptor peptide (PDB: 1G1H; red). The conserved water molecule found in closed structures is shown: PTP1B (1SUG, yellow); GLEPP1 (2G59, orange); HePTP (2A3K, black), DEP1 (2NZ6, magenta). The arrow indicates the position of the displaced water molecule in STEP-C/S structure.
Figure 4.
Figure 4. Secondary Substrate-Binding Pockets
(A) Two extreme conformations of the second-site loop are shown (orange) from RPTPγ (extended helix) and HEPTP (closed in conformation). The catalytic cysteine is shown in a space-filling CPK representation, and loops are colored as follows: WPD (magenta), β5/β6 loop (green), and gateway (red). The dually pTyr phosphorylated insulin receptor peptide (from PDB: 1G1H) is shown superimposed (for reference only) to indicate the position of the secondary substrate-binding pocket. The positions of Arg24 and gateway residues Met258 and Gly259 of PTP1B are shown in an enlarged view.
(B) Surface topology and electrostatic charge for the active site (pY), gateway region, and secondary pocket (2pY) are shown for each of the five categories with the dually pTyr phosphorylated insulin receptor peptide superimposed.
(C) Representative second-site loop conformations are shown for each category (see also Supplemental Data). Category I: SHP2, BDP1, LYP; Category II: IA2, IA2β; Category III: LAR, RPTPσ; Category IV: PTPH1, MEG1, PTPD2, CD45; Category V: STEP, HEPTP, PCPTP1.
 
  The above figures are reprinted from an Open Access publication published by Cell Press: Cell (2009, 136, 352-363) copyright 2009.  
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21123182 E.Ferrari, M.Tinti, S.Costa, S.Corallino, A.P.Nardozza, A.Chatraryamontri, A.Ceol, G.Cesareni, and L.Castagnoli (2011).
Identification of new substrates of the protein-tyrosine phosphatase PTP1B by Bayesian integration of proteome evidence.
  J Biol Chem, 286, 4173-4185.  
21112398 H.Hashemi, M.Hurley, A.Gibson, V.Panova, V.Tchetchelnitski, A.Barr, and A.W.Stoker (2011).
Receptor tyrosine phosphatase PTPγ is a regulator of spinal cord neurogenesis.
  Mol Cell Neurosci, 46, 469-482.  
21179176 S.G.Julien, N.Dubé, S.Hardy, and M.L.Tremblay (2011).
Inside the human cancer tyrosine phosphatome.
  Nat Rev Cancer, 11, 35-49.  
21190897 S.J.Davis, and P.A.van der Merwe (2011).
Lck and the nature of the T cell receptor trigger.
  Trends Immunol, 32, 1-5.  
21276943 S.Liu, Z.Yu, X.Yu, S.X.Huang, Y.Luo, L.Wu, W.Shen, Z.Yang, L.Wang, A.M.Gunawan, R.J.Chan, B.Shen, and Z.Y.Zhang (2011).
SHP2 is a target of the immunosuppressant tautomycetin.
  Chem Biol, 18, 101-110.  
21420867 V.V.Vintonyak, H.Waldmann, and D.Rauh (2011).
Using small molecules to target protein phosphatases.
  Bioorg Med Chem, 19, 2145-2155.  
21074407 E.Zeqiraj, and D.M.van Aalten (2010).
Pseudokinases-remnants of evolution or key allosteric regulators?
  Curr Opin Struct Biol, 20, 772-781.  
20432460 K.Mahajan, and N.P.Mahajan (2010).
Shepherding AKT and androgen receptor by Ack1 tyrosine kinase.
  J Cell Physiol, 224, 327-333.  
20813251 R.A.Fernandes, C.Yu, A.M.Carmo, E.J.Evans, P.A.van der Merwe, and S.J.Davis (2010).
What controls T cell receptor phosphorylation?
  Cell, 142, 668-669.  
20133774 S.Bouyain, and D.J.Watkins (2010).
The protein tyrosine phosphatases PTPRZ and PTPRG bind to distinct members of the contactin family of neural recognition molecules.
  Proc Natl Acad Sci U S A, 107, 2443-2448.
PDB codes: 3jxa 3jxf 3jxg 3jxh 3kld
  20714415 S.Bouyain, and D.J.Watkins (2010).
Identification of tyrosine phosphatase ligands for contactin cell adhesion molecules.
  Commun Integr Biol, 3, 284-286.  
  20360941 S.M.Burden-Gulley, T.J.Gates, A.M.Burgoyne, J.L.Cutter, D.T.Lodowski, S.Robinson, A.E.Sloan, R.H.Miller, J.P.Basilion, and S.M.Brady-Kalnay (2010).
A novel molecular diagnostic of glioblastomas: detection of an extracellular fragment of protein tyrosine phosphatase mu.
  Neoplasia, 12, 305-316.  
20170098 X.Zhang, Y.He, S.Liu, Z.Yu, Z.X.Jiang, Z.Yang, Y.Dong, S.C.Nabinger, L.Wu, A.M.Gunawan, L.Wang, R.J.Chan, and Z.Y.Zhang (2010).
Salicylic acid based small molecule inhibitor for the oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2).
  J Med Chem, 53, 2482-2493.
PDB codes: 3jrl 3o5x
19573017 A.E.Hower, P.J.Beltran, and J.L.Bixby (2009).
Dimerization of tyrosine phosphatase PTPRO decreases its activity and ability to inactivate TrkC.
  J Neurochem, 110, 1635-1647.  
19489729 A.Edwards (2009).
Large-scale structural biology of the human proteome.
  Annu Rev Biochem, 78, 541-568.  
19716756 D.Krishnamurthy, and A.M.Barrios (2009).
Profiling protein tyrosine phosphatase activity with mechanistic probes.
  Curr Opin Chem Biol, 13, 375-381.  
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.  
19494114 F.Sacco, M.Tinti, A.Palma, E.Ferrari, A.P.Nardozza, R.Hooft van Huijsduijnen, T.Takahashi, L.Castagnoli, and G.Cesareni (2009).
Tumor suppressor density-enhanced phosphatase-1 (DEP-1) inhibits the RAS pathway by direct dephosphorylation of ERK1/2 kinases.
  J Biol Chem, 284, 22048-22058.  
19721463 J.Weigelt (2009).
The case for open-access chemical biology. A strategy for pre-competitive medicinal chemistry to promote drug discovery.
  EMBO Rep, 10, 941-945.  
19889974 K.Hofmeyer, and J.E.Treisman (2009).
The receptor protein tyrosine phosphatase LAR promotes R7 photoreceptor axon targeting by a phosphatase-independent signaling mechanism.
  Proc Natl Acad Sci U S A, 106, 19399-19404.  
19340315 M.C.Gingras, Y.L.Zhang, D.Kharitidi, A.J.Barr, S.Knapp, M.L.Tremblay, and A.Pause (2009).
HD-PTP is a catalytically inactive tyrosine phosphatase due to a conserved divergence in its phosphatase domain.
  PLoS ONE, 4, e5105.  
19351884 N.Krishnan, D.G.Jeong, S.K.Jung, S.E.Ryu, A.Xiao, C.D.Allis, S.J.Kim, and N.K.Tonks (2009).
Dephosphorylation of the C-terminal Tyrosyl Residue of the DNA Damage-related Histone H2A.X Is Mediated by the Protein Phosphatase Eyes Absent.
  J Biol Chem, 284, 16066-16070.  
19371084 S.J.Tsai, U.Sen, L.Zhao, W.B.Greenleaf, J.Dasgupta, E.Fiorillo, V.Orrú, N.Bottini, and X.S.Chen (2009).
Crystal structure of the human lymphoid tyrosine phosphatase catalytic domain: insights into redox regulation .
  Biochemistry, 48, 4838-4845.
PDB code: 3h2x
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
19843518 Y.Tong, P.K.Hota, J.Y.Penachioni, M.B.Hamaneh, S.Kim, R.S.Alviani, L.Shen, H.He, W.Tempel, L.Tamagnone, H.W.Park, and M.Buck (2009).
Structure and function of the intracellular region of the plexin-b1 transmembrane receptor.
  J Biol Chem, 284, 35962-35972.
PDB code: 3hm6
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.