PDBsum entry 1oet

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Hydrolase PDB id
Protein chain
281 a.a. *
Waters ×264
* Residue conservation analysis
PDB id:
Name: Hydrolase
Title: Oxidation state of protein tyrosine phosphatase 1b
Structure: -Tyrosine phosphatase, non-receptor type 1. Chain: a. Fragment: catalytic domain, residues 1-321. Synonym: protein-tyrosine phosphatase 1b, ptp-1b. Engineered: yes. Other_details: cys215 has been modified to sulfenic acid (cys-soh)
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 511693. Expression_system_variant: de3. Other_details: residues 1-321
2.30Å     R-factor:   0.171     R-free:   0.226
Authors: R.L.M.Van Montfort,M.Congreve,D.Tisi,R.Carr,H.Jhoti
Key ref:
R.L.van Montfort et al. (2003). Oxidation state of the active-site cysteine in protein tyrosine phosphatase 1B. Nature, 423, 773-777. PubMed id: 12802339 DOI: 10.1038/nature01681
31-Mar-03     Release date:   12-Jun-03    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P18031  (PTN1_HUMAN) -  Tyrosine-protein phosphatase non-receptor type 1
435 a.a.
281 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: 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
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  


DOI no: 10.1038/nature01681 Nature 423:773-777 (2003)
PubMed id: 12802339  
Oxidation state of the active-site cysteine in protein tyrosine phosphatase 1B.
R.L.van Montfort, M.Congreve, D.Tisi, R.Carr, H.Jhoti.
Protein tyrosine phosphatases regulate signal transduction pathways involving tyrosine phosphorylation and have been implicated in the development of cancer, diabetes, rheumatoid arthritis and hypertension. Increasing evidence suggests that the cellular redox state is involved in regulating tyrosine phosphatase activity through the reversible oxidization of the catalytic cysteine to sulphenic acid (Cys-SOH). But how further oxidation to the irreversible sulphinic (Cys-SO2H) and sulphonic (Cys-SO3H) forms is prevented remains unclear. Here we report the crystal structures of the regulatory sulphenic and irreversible sulphinic and sulphonic acids of protein tyrosine phosphatase 1B (PTP1B), an important enzyme in the negative regulation of the insulin receptor and a therapeutic target in type II diabetes and obesity. We also identify a sulphenyl-amide species that is formed through oxidation of its catalytic cysteine. Formation of the sulphenyl-amide causes large changes in the PTP1B active site, which are reversible by reduction with the cellular reducing agent glutathione. The sulphenyl-amide is a protective intermediate in the oxidative inhibition of PTP1B. In addition, it may facilitate reactivation of PTP1B by biological thiols and signal a unique state of the protein.
  Selected figure(s)  
Figure 1.
Figure 1: Comparison of native and sulphenyl-amide PTP1B. a, Ribbon diagram of PTP1B. The phosphate-binding cradle is shown in red, the WPD loop in green and the pTyr recognition loop in gold. b, Superposition of native PTP1B (blue) and the sulphenyl-amide-containing structure (orange), showing different conformations of the pTyr recognition loop and the phosphate-binding cradle. c, Electron density of the catalytic cysteine and its neighbouring residues in reduced PTP1B (see Supplementary Information). d, Electron density of the newly identified sulphenyl-amide derivative of Cys 215. The electron density maps in c and d are contoured at 1 . All figures are generated using Aesop (M. Noble, Laboratory of Molecular Biophysics, University of Oxford, unpublished).
Figure 2.
Figure 2: Putative mechanism of sulphenyl-amide formation and subsequent reactivation. The catalytic cysteine of PTP1B (E -SH) is oxidized to a sulphenic acid (E -S -OH). The sulphenyl-amide may be formed by a direct mechanism involving a nucleophilic attack of the backbone nitrogen of Ser 216 on the S atom of Cys 215 and subsequent release of water. Alternatively, the sulphenic acid may be oxidized to a highly reactive intermediate by H[2]O[2] or an oxidized thiol, which then reacts to give the sulphenyl-amide. Reactivation of the enzyme occurs via mixed disulphide formation with a thiol. R, glutathione or DTT; X, leaving group OOH (sulphenoperoxoic acid) or OS(O)R (sulphinothioic acid).
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nature (2003, 423, 773-777) copyright 2003.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

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19187004 D.F.Stowe, and A.K.Camara (2009).
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PDB code: 3h2x
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The role of glutathione in photosynthetic organisms: emerging functions for glutaredoxins and glutathionylation.
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18280234 P.Herrlich, M.Karin, and C.Weiss (2008).
Supreme EnLIGHTenment: damage recognition and signaling in the mammalian UV response.
  Mol Cell, 29, 279-290.  
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Redox regulation of interleukin-4 signaling.
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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
18595691 S.Bhattacharya, J.N.Labutti, D.R.Seiner, and K.S.Gates (2008).
Oxidative inactivation of protein tyrosine phosphatase 1B by organic hydroperoxides.
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18545666 S.Galli, V.G.Antico Arciuch, C.Poderoso, D.P.Converso, Q.Zhou, E.Bal de Kier Joffé, E.Cadenas, J.Boczkowski, M.C.Carreras, and J.J.Poderoso (2008).
Tumor cell phenotype is sustained by selective MAPK oxidation in mitochondria.
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18363800 S.Soonsanga, J.W.Lee, and J.D.Helmann (2008).
Oxidant-dependent switching between reversible and sacrificial oxidation pathways for Bacillus subtilis OhrR.
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18436649 T.Nakamura, T.Yamamoto, M.Abe, H.Matsumura, Y.Hagihara, T.Goto, T.Yamaguchi, and T.Inoue (2008).
Oxidation of archaeal peroxiredoxin involves a hypervalent sulfur intermediate.
  Proc Natl Acad Sci U S A, 105, 6238-6242.
PDB codes: 2e2g 2e2m 2nvl 2zct
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A food-derived synergist of NGF signaling: identification of protein tyrosine phosphatase 1B as a key regulator of NGF receptor-initiated signal transduction.
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Cysteine S-Nitrosylation Protects Protein-tyrosine Phosphatase 1B against Oxidation-induced Permanent Inactivation.
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PDB code: 3eu0
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Kinetic and structural analysis of a bacterial protein tyrosine phosphatase-like myo-inositol polyphosphatase.
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PDB codes: 2b4o 2b4p 2b4u
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ROS as signalling molecules: mechanisms that generate specificity in ROS homeostasis.
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Hydrogen peroxide sensing and signaling.
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Zn2+-dependent redox switch in the intracellular T1-T1 interface of a Kv channel.
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Use and abuse of exogenous H2O2 in studies of signal transduction.
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A novel salt bridge mechanism highlights the need for nonmobile proton conditions to promote disulfide bond cleavage in protonated peptides under low-energy collisional activation.
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Sulfenic acid in human serum albumin.
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Aspects of the biological redox chemistry of cysteine: from simple redox responses to sophisticated signalling pathways.
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17081112 C.von Montfort, V.S.Sharov, S.Metzger, C.Schöneich, H.Sies, and L.O.Klotz (2006).
Singlet oxygen inactivates protein tyrosine phosphatase-1B by oxidation of the active site cysteine.
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16677071 J.R.Stone, and S.Yang (2006).
Hydrogen peroxide: a signaling messenger.
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Regulation of signal transduction through protein cysteine oxidation.
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Redox activation of aldose reductase in the ischemic heart.
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Reactive oxygen species in cardiac signalling: from mitochondria to plasma membrane ion channels.
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Protein tyrosine phosphatases: from genes, to function, to disease.
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16369939 N.W.Blackstone (2006).
Multicellular redox regulation: integrating organismal biology and redox chemistry.
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16278309 R.Gupta, S.Karpatkin, and R.S.Basch (2006).
Hematopoiesis and stem cell renewal in long-term bone marrow cultures containing catalase.
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Redox regulation in anabolic and catabolic processes.
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Protection against oxidant-induced apoptosis by mitochondrial thioredoxin in SH-SY5Y neuroblastoma cells.
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16849327 Y.Xu, Y.Shao, J.J.Voorhees, and G.J.Fisher (2006).
Oxidative inhibition of receptor-type protein-tyrosine phosphatase kappa by ultraviolet irradiation activates epidermal growth factor receptor in human keratinocytes.
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15843166 A.Barthel, and L.O.Klotz (2005).
Phosphoinositide 3-kinase signaling in the cellular response to oxidative stress.
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15623519 A.Groen, S.Lemeer, T.van der Wijk, J.Overvoorde, A.J.Heck, A.Ostman, D.Barford, M.Slijper, and J.den Hertog (2005).
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15787978 A.S.Müller, E.Most, and J.Pallauf (2005).
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15890001 A.Salmeen, and D.Barford (2005).
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15677487 B.J.Goldstein, K.Mahadev, M.Kalyankar, and X.Wu (2005).
Redox paradox: insulin action is facilitated by insulin-stimulated reactive oxygen species with multiple potential signaling targets.
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15998257 B.J.Goldstein, K.Mahadev, X.Wu, L.Zhu, and H.Motoshima (2005).
Role of insulin-induced reactive oxygen species in the insulin signaling pathway.
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16306267 C.E.McCartney, H.McClafferty, J.M.Huibant, E.G.Rowan, M.J.Shipston, and I.C.Rowe (2005).
A cysteine-rich motif confers hypoxia sensitivity to mammalian large conductance voltage- and Ca-activated K (BK) channel alpha-subunits.
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16271885 C.Grundner, H.L.Ng, and T.Alber (2005).
Mycobacterium tuberculosis protein tyrosine phosphatase PtpB structure reveals a diverged fold and a buried active site.
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PDB code: 1ywf
15579467 D.J.Levinthal, and D.B.Defranco (2005).
Reversible oxidation of ERK-directed protein phosphatases drives oxidative toxicity in neurons.
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15570599 D.Luo, S.W.Smith, and B.D.Anderson (2005).
Kinetics and mechanism of the reaction of cysteine and hydrogen peroxide in aqueous solution.
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16158225 H.Haase, and W.Maret (2005).
Protein tyrosine phosphatases as targets of the combined insulinomimetic effects of zinc and oxidants.
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15766528 H.Kamata, S.Honda, S.Maeda, L.Chang, H.Hirata, and M.Karin (2005).
Reactive oxygen species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases.
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15389864 I.Dalle-Donne, A.Scaloni, D.Giustarini, E.Cavarra, G.Tell, G.Lungarella, R.Colombo, R.Rossi, and A.Milzani (2005).
Proteins as biomarkers of oxidative/nitrosative stress in diseases: the contribution of redox proteomics.
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15650395 I.Rahman, S.K.Biswas, L.A.Jimenez, M.Torres, and H.J.Forman (2005).
Glutathione, stress responses, and redox signaling in lung inflammation.
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15933714 J.Kwon, C.K.Qu, J.S.Maeng, R.Falahati, C.Lee, and M.S.Williams (2005).
Receptor-stimulated oxidation of SHP-2 promotes T-cell adhesion through SLP-76-ADAP.
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15998259 J.L.Evans, B.A.Maddux, and I.D.Goldfine (2005).
The molecular basis for oxidative stress-induced insulin resistance.
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16200195 J.L.Luo, H.Kamata, and M.Karin (2005).
IKK/NF-kappaB signaling: balancing life and death--a new approach to cancer therapy.
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16380818 J.L.Luo, H.Kamata, and M.Karin (2005).
The anti-death machinery in IKK/NF-kappaB signaling.
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15890022 J.Rudolph (2005).
Redox regulation of the Cdc25 phosphatases.
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15890002 P.Chiarugi, and E.Giannoni (2005).
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16317705 P.Dent, Y.Fang, S.Gupta, E.Studer, C.Mitchell, S.Spiegel, and P.B.Hylemon (2005).
Conjugated bile acids promote ERK1/2 and AKT activation via a pertussis toxin-sensitive mechanism in murine and human hepatocytes.
  Hepatology, 42, 1291-1299.  
15998249 R.E.Shackelford, A.N.Heinloth, S.C.Heard, and R.S.Paules (2005).
Cellular and molecular targets of protein S-glutathiolation.
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15780595 S.G.Rhee, S.W.Kang, W.Jeong, T.S.Chang, K.S.Yang, and H.A.Woo (2005).
Intracellular messenger function of hydrogen peroxide and its regulation by peroxiredoxins.
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15998263 S.J.Salsman, K.Hensley, and R.A.Floyd (2005).
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15630428 T.Mustelin, T.Vang, and N.Bottini (2005).
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15998262 W.Dröge (2005).
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15778445 Y.Li, W.P.Yu, C.W.Lin, and T.Y.Chen (2005).
Oxidation and reduction control of the inactivation gating of Torpedo ClC-0 chloride channels.
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15134754 C.Laloi, K.Apel, and A.Danon (2004).
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14762163 C.Persson, T.Sjöblom, A.Groen, K.Kappert, U.Engström, U.Hellman, C.H.Heldin, J.den Hertog, and A.Ostman (2004).
Preferential oxidation of the second phosphatase domain of receptor-like PTP-alpha revealed by an antibody against oxidized protein tyrosine phosphatases.
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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.
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PDB code: 1r6h
15024017 I.K.Lund, H.S.Andersen, L.F.Iversen, O.H.Olsen, K.B.Møller, A.K.Pedersen, Y.Ge, D.D.Holsworth, M.J.Newman, F.U.Axe, and N.P.Møller (2004).
Structure-based design of selective and potent inhibitors of protein-tyrosine phosphatase beta.
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15151929 J.Seligman, Y.Zipser, and N.S.Kosower (2004).
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15352167 J.V.Cross, and D.J.Templeton (2004).
Thiol oxidation of cell signaling proteins: Controlling an apoptotic equilibrium.
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15377225 K.Apel, and H.Hirt (2004).
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Protein sulfenic acids in redox signaling.
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15110387 O.Augusto, M.G.Bonini, and D.Trindade (2004).
Spin trapping of glutathiyl and protein radicals produced from nitric oxide-derived oxidants.
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15247926 P.Gulati, B.Markova, M.Göttlicher, F.D.Böhmer, and P.A.Herrlich (2004).
UVA inactivates protein tyrosine phosphatases by calpain-mediated degradation.
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H2O2-induced intermolecular disulfide bond formation between receptor protein-tyrosine phosphatases.
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14670964 X.Fu, J.L.Kao, C.Bergt, S.Y.Kassim, N.P.Huq, A.d'Avignon, W.C.Parks, R.P.Mecham, and J.W.Heinecke (2004).
Oxidative cross-linking of tryptophan to glycine restrains matrix metalloproteinase activity: specific structural motifs control protein oxidation.
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Bile acids induce mitochondrial ROS, which promote activation of receptor tyrosine kinases and signaling pathways in rat hepatocytes.
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14504278 Q.Wang, G.R.Pfeiffer, and W.A.Gaarde (2003).
Activation of SRC tyrosine kinases in response to ICAM-1 ligation in pulmonary microvascular endothelial cells.
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Transactivation joins multiple tracks to the ERK/MAPK cascade.
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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.