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PDBsum entry 1pty

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protein ligands metals links
Hydrolase PDB id
1pty
Jmol
Contents
Protein chain
298 a.a. *
Ligands
PTR ×2
Metals
_MG
Waters ×263
* Residue conservation analysis
PDB id:
1pty
Name: Hydrolase
Title: Crystal structure of protein tyrosine phosphatase 1b complexed with two phosphotyrosine molecules
Structure: Protein tyrosine phosphatase 1b. Chain: a. Synonym: ptp1b. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Cell_line: bl21. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
Resolution:
1.85Å     R-factor:   0.181    
Authors: Y.Zhao,Y.A.Puius,M.Sullivan,D.Lawrence,S.C.Almo,Z.-Y.Zhang
Key ref:
Y.A.Puius et al. (1997). Identification of a second aryl phosphate-binding site in protein-tyrosine phosphatase 1B: a paradigm for inhibitor design. Proc Natl Acad Sci U S A, 94, 13420-13425. PubMed id: 9391040 DOI: 10.1073/pnas.94.25.13420
Date:
16-Jan-97     Release date:   21-Jan-98    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P18031  (PTN1_HUMAN) -  Tyrosine-protein phosphatase non-receptor type 1
Seq:
Struc:
435 a.a.
298 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.3.1.3.48  - Protein-tyrosine-phosphatase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Protein tyrosine phosphate + H2O = protein tyrosine + phosphate
Protein tyrosine phosphate
Bound ligand (Het Group name = PTR)
matches with 72.00% similarity
+ 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: 10.1073/pnas.94.25.13420 Proc Natl Acad Sci U S A 94:13420-13425 (1997)
PubMed id: 9391040  
 
 
Identification of a second aryl phosphate-binding site in protein-tyrosine phosphatase 1B: a paradigm for inhibitor design.
Y.A.Puius, Y.Zhao, M.Sullivan, D.S.Lawrence, S.C.Almo, Z.Y.Zhang.
 
  ABSTRACT  
 
The structure of the catalytically inactive mutant (C215S) of the human protein-tyrosine phosphatase 1B (PTP1B) has been solved to high resolution in two complexes. In the first, crystals were grown in the presence of bis-(para-phosphophenyl) methane (BPPM), a synthetic high-affinity low-molecular weight nonpeptidic substrate (Km = 16 microM), and the structure was refined to an R-factor of 18. 2% at 1.9 A resolution. In the second, crystals were grown in a saturating concentration of phosphotyrosine (pTyr), and the structure was refined to an R-factor of 18.1% at 1.85 A. Difference Fourier maps showed that BPPM binds PTP1B in two mutually exclusive modes, one in which it occupies the canonical pTyr-binding site (the active site), and another in which a phosphophenyl moiety interacts with a set of residues not previously observed to bind aryl phosphates. The identification of a second pTyr molecule at the same site in the PTP1B/C215S-pTyr complex confirms that these residues constitute a low-affinity noncatalytic aryl phosphate-binding site. Identification of a second aryl phosphate binding site adjacent to the active site provides a paradigm for the design of tight-binding, highly specific PTP1B inhibitors that can span both the active site and the adjacent noncatalytic site. This design can be achieved by tethering together two small ligands that are individually targeted to the active site and the proximal noncatalytic site.
 
  Selected figure(s)  
 
Figure 3.
Fig. 3. Stereo representations of the binding modes of BPPM A (a), BPPM B (b), and pTyr B (c). Contacts represented by dashed lines are distances less than 3.6 Å, except for certain interactions with aromatic rings. Interactions between the amide nitrogens of residues 216-221 and the phosphate groups of ligand A are too numerous to represent. [Diagrams were generated with the program O (16)].
Figure 4.
Fig. 4. Schematic representations of the interactions between PTP1B/C215S and BPPM A (a), BPPM B (b), and pTyr B (c). A distance cutoff^ of 3.6 Å was used, except for certain interactions with aromatic^ rings.
 
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21453996 J.J.Ramírez-Espinosa, M.Y.Rios, S.López-Martínez, F.López-Vallejo, J.L.Medina-Franco, P.Paoli, G.Camici, G.Navarrete-Vázquez, R.Ortiz-Andrade, and S.Estrada-Soto (2011).
Antidiabetic activity of some pentacyclic acid triterpenoids, role of PTP-1B: in vitro, in silico, and in vivo approaches.
  Eur J Med Chem, 46, 2243-2251.  
20389282 A.Manford, T.Xia, A.K.Saxena, C.Stefan, F.Hu, S.D.Emr, and Y.Mao (2010).
Crystal structure of the yeast Sac1: implications for its phosphoinositide phosphatase function.
  EMBO J, 29, 1489-1498.
PDB code: 3lwt
20644889 K.A.Rawls, C.Grundner, and J.A.Ellman (2010).
Design and synthesis of nonpeptidic, small molecule inhibitors for the Mycobacterium tuberculosis protein tyrosine phosphatase PtpB.
  Org Biomol Chem, 8, 4066-4070.  
20617368 L.Lu, S.Wang, M.Zhu, Z.Liu, M.Guo, S.Xing, and X.Fu (2010).
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  Biometals, 23, 1139-1147.  
20205445 R.G.Coleman, and K.A.Sharp (2010).
Protein pockets: inventory, shape, and comparison.
  J Chem Inf Model, 50, 589-603.  
20957718 R.He, Z.Yu, Y.He, L.F.Zeng, J.Xu, L.Wu, A.M.Gunawan, L.Wang, Z.X.Jiang, and Z.Y.Zhang (2010).
Double click reaction for the acquisition of a highly potent and selective mPTPB inhibitor.
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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
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Large-scale structural analysis of the classical human protein tyrosine phosphatome.
  Cell, 136, 352-363.
PDB codes: 2ahs 2b49 2cfv 2cjz 2gjt 2h4v 2i75 2jjd 2nlk 2nz6 2oc3 2ooq 2p6x 2pa5 2qep 3b7o
19381599 C.Walls, B.Zhou, and Z.Y.Zhang (2009).
Activity-based protein profiling of protein tyrosine phosphatases.
  Methods Mol Biol, 519, 417-429.  
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.  
19240079 N.J.Beresford, D.Mulhearn, B.Szczepankiewicz, G.Liu, M.E.Johnson, A.Fordham-Skelton, C.Abad-Zapatero, J.S.Cavet, and L.Tabernero (2009).
Inhibition of MptpB phosphatase from Mycobacterium tuberculosis impairs mycobacterial survival in macrophages.
  J Antimicrob Chemother, 63, 928-936.  
19288492 R.Maccari, R.Ottanà, R.Ciurleo, P.Paoli, G.Manao, G.Camici, C.Laggner, and T.Langer (2009).
Structure-based optimization of benzoic acids as inhibitors of protein tyrosine phosphatase 1B and low molecular weight protein tyrosine phosphatase.
  ChemMedChem, 4, 957-962.  
19590777 R.Srinivasan, L.P.Tan, H.Wu, P.Y.Yang, K.A.Kalesh, and S.Q.Yao (2009).
High-throughput synthesis of azide libraries suitable for direct "click" chemistry and in situ screening.
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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.  
18685809 K.Bharatham, N.Bharatham, Y.J.Kwon, and K.W.Lee (2008).
Molecular dynamics simulation study of PTP1B with allosteric inhibitor and its application in receptor based pharmacophore modeling.
  J Comput Aided Mol Des, 22, 925-933.  
18298793 L.Tabernero, A.R.Aricescu, E.Y.Jones, and S.E.Szedlacsek (2008).
Protein tyrosine phosphatases: structure-function relationships.
  FEBS J, 275, 867-882.  
19012396 S.Liu, L.F.Zeng, L.Wu, X.Yu, T.Xue, A.M.Gunawan, Y.Q.Long, and Z.Y.Zhang (2008).
Targeting inactive enzyme conformation: aryl diketoacid derivatives as a new class of PTP1B inhibitors.
  J Am Chem Soc, 130, 17075-17084.
PDB codes: 3eax 3eb1
18555856 Z.Q.Wang, D.Ribnicky, X.H.Zhang, I.Raskin, Y.Yu, and W.T.Cefalu (2008).
Bioactives of Artemisia dracunculus L enhance cellular insulin signaling in primary human skeletal muscle culture.
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17596826 A.K.Nordle, P.Rios, A.Gaulton, R.Pulido, T.K.Attwood, and L.Tabernero (2007).
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  Proteins, 69, 19-31.  
17437721 C.Grundner, D.Perrin, R.Hooft van Huijsduijnen, D.Swinnen, J.Gonzalez, C.L.Gee, T.N.Wells, and T.Alber (2007).
Structural basis for selective inhibition of Mycobacterium tuberculosis protein tyrosine phosphatase PtpB.
  Structure, 15, 499-509.
PDB code: 2oz5
17046267 J.Xie, and C.T.Seto (2007).
A two stage click-based library of protein tyrosine phosphatase inhibitors.
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17191286 M.Stuible, L.Zhao, I.Aubry, D.Schmidt-Arras, F.D.Böhmer, C.J.Li, and M.L.Tremblay (2007).
Cellular inhibition of protein tyrosine phosphatase 1B by uncharged thioxothiazolidinone derivatives.
  Chembiochem, 8, 179-186.  
17543532 R.Maccari, P.Paoli, R.Ottanà, M.Jacomelli, R.Ciurleo, G.Manao, T.Steindl, T.Langer, M.G.Vigorita, and G.Camici (2007).
5-Arylidene-2,4-thiazolidinediones as inhibitors of protein tyrosine phosphatases.
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18058037 S.C.Almo, J.B.Bonanno, J.M.Sauder, S.Emtage, T.P.Dilorenzo, V.Malashkevich, S.R.Wasserman, S.Swaminathan, S.Eswaramoorthy, R.Agarwal, D.Kumaran, M.Madegowda, S.Ragumani, Y.Patskovsky, J.Alvarado, U.A.Ramagopal, J.Faber-Barata, M.R.Chance, A.Sali, A.Fiser, Z.Y.Zhang, D.S.Lawrence, and S.K.Burley (2007).
Structural genomics of protein phosphatases.
  J Struct Funct Genomics, 8, 121-140.
PDB codes: 1rxd 2fh7 2g59 2hcm 2hhl 2hxp 2hy3 2i0o 2i1y 2i44 2iq1 2irm 2isn 2nv5 2oyc 2p27 2p4u 2p69 2p8e 2pbn 2q5e 2qjc 2r0b
17400920 X.Tao, and L.Tong (2007).
Crystal structure of the MAP kinase binding domain and the catalytic domain of human MKP5.
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PDB codes: 2ouc 2oud
18056643 X.Yu, J.P.Sun, Y.He, X.Guo, S.Liu, B.Zhou, A.Hudmon, and Z.Y.Zhang (2007).
Structure, inhibitor, and regulatory mechanism of Lyp, a lymphoid-specific tyrosine phosphatase implicated in autoimmune diseases.
  Proc Natl Acad Sci U S A, 104, 19767-19772.  
16534812 A.J.Barr, J.E.Debreczeni, J.Eswaran, and S.Knapp (2006).
Crystal structure of human protein tyrosine phosphatase 14 (PTPN14) at 1.65-A resolution.
  Proteins, 63, 1132-1136.
PDB code: 2bzl
17008719 D.Tolkatchev, R.Shaykhutdinov, P.Xu, J.Plamondon, D.C.Watson, N.M.Young, and F.Ni (2006).
Three-dimensional structure and ligand interactions of the low molecular weight protein tyrosine phosphatase from Campylobacter jejuni.
  Protein Sci, 15, 2381-2394.
PDB code: 2gi4
16364216 G.X.Liu, J.Z.Tan, C.Y.Niu, J.H.Shen, X.M.Luo, X.Shen, K.X.Chen, and H.L.Jiang (2006).
Molecular dynamics simulations of interaction between protein-tyrosine phosphatase 1B and a bidentate inhibitor.
  Acta Pharmacol Sin, 27, 100-110.  
16240315 L.Milanesi, C.A.Hunter, S.E.Sedelnikova, and J.P.Waltho (2006).
Amplification of bifunctional ligands for calmodulin from a dynamic combinatorial library.
  Chemistry, 12, 1081-1087.  
16891175 T.Motiwala, and S.T.Jacob (2006).
Role of protein tyrosine phosphatases in cancer.
  Prog Nucleic Acid Res Mol Biol, 81, 297-329.  
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.
  Diabetes, 54, 311-321.  
15608376 R.A.Judge, K.Swift, and C.González (2005).
An ultraviolet fluorescence-based method for identifying and distinguishing protein crystals.
  Acta Crystallogr D Biol Crystallogr, 61, 60-66.  
16235263 R.G.Coleman, M.A.Burr, D.L.Souvaine, and A.C.Cheng (2005).
An intuitive approach to measuring protein surface curvature.
  Proteins, 61, 1068-1074.  
16271887 S.Li, R.S.Depetris, D.Barford, J.Chernoff, and S.R.Hubbard (2005).
Crystal structure of a complex between protein tyrosine phosphatase 1B and the insulin receptor tyrosine kinase.
  Structure, 13, 1643-1651.
PDB code: 2b4s
16013076 U.Schieborr, M.Vogtherr, B.Elshorst, M.Betz, S.Grimme, B.Pescatore, T.Langer, K.Saxena, and H.Schwalbe (2005).
How much NMR data is required to determine a protein-ligand complex structure?
  Chembiochem, 6, 1891-1898.  
15258570 C.Wiesmann, K.J.Barr, J.Kung, J.Zhu, D.A.Erlanson, W.Shen, B.J.Fahr, M.Zhong, L.Taylor, M.Randal, R.S.McDowell, and S.K.Hansen (2004).
Allosteric inhibition of protein tyrosine phosphatase 1B.
  Nat Struct Mol Biol, 11, 730-737.
PDB codes: 1t48 1t49 1t4j
15013940 S.D.Taylor, and B.Hill (2004).
Recent advances in protein tyrosine phosphatase 1B inhibitors.
  Expert Opin Investig Drugs, 13, 199-214.  
14517908 A.Nayeem, S.Krystek, and T.Stouch (2003).
An assessment of protein-ligand binding site polarizability.
  Biopolymers, 70, 201-211.  
12804696 K.Umezawa, M.Kawakami, and T.Watanabe (2003).
Molecular design and biological activities of protein-tyrosine phosphatase inhibitors.
  Pharmacol Ther, 99, 15-24.  
12556216 Z.Y.Zhang, and S.Y.Lee (2003).
PTP1B inhibitors as potential therapeutics in the treatment of type 2 diabetes and obesity.
  Expert Opin Investig Drugs, 12, 223-233.  
12186556 H.Fu, J.Park, and D.Pei (2002).
Peptidyl aldehydes as reversible covalent inhibitors of protein tyrosine phosphatases.
  Biochemistry, 41, 10700-10709.  
11900546 L.Xie, Y.L.Zhang, and Z.Y.Zhang (2002).
Design and characterization of an improved protein tyrosine phosphatase substrate-trapping mutant.
  Biochemistry, 41, 4032-4039.  
12546919 R.Hooft van Huijsduijnen, A.Bombrun, and D.Swinnen (2002).
Selecting protein tyrosine phosphatases as drug targets.
  Drug Discov Today, 7, 1013-1019.  
12209150 T.O.Johnson, J.Ermolieff, and M.R.Jirousek (2002).
Protein tyrosine phosphatase 1B inhibitors for diabetes.
  Nat Rev Drug Discov, 1, 696-709.  
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.  
11468356 G.Scapin, S.Patel, V.Patel, B.Kennedy, and E.Asante-Appiah (2001).
The structure of apo protein-tyrosine phosphatase 1B C215S mutant: more than just an S --> O change.
  Protein Sci, 10, 1596-1605.
PDB code: 1i57
11585896 J.N.Andersen, O.H.Mortensen, G.H.Peters, P.G.Drake, L.F.Iversen, O.H.Olsen, P.G.Jansen, H.S.Andersen, N.K.Tonks, and N.P.Møller (2001).
Structural and evolutionary relationships among protein tyrosine phosphatase domains.
  Mol Cell Biol, 21, 7117-7136.  
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.  
11470605 Z.Y.Zhang (2001).
Protein tyrosine phosphatases: prospects for therapeutics.
  Curr Opin Chem Biol, 5, 416-423.  
11163213 A.Salmeen, J.N.Andersen, M.P.Myers, N.K.Tonks, and D.Barford (2000).
Molecular basis for the dephosphorylation of the activation segment of the insulin receptor by protein tyrosine phosphatase 1B.
  Mol Cell, 6, 1401-1412.
PDB codes: 1g1f 1g1g 1g1h
10974195 B.P.Kennedy, and C.Ramachandran (2000).
Protein tyrosine phosphatase-1B in diabetes.
  Biochem Pharmacol, 60, 877-883.  
10889023 M.Sarmiento, Y.A.Puius, S.W.Vetter, Y.F.Keng, L.Wu, Y.Zhao, D.S.Lawrence, S.C.Almo, and Z.Y.Zhang (2000).
Structural basis of plasticity in protein tyrosine phosphatase 1B substrate recognition.
  Biochemistry, 39, 8171-8179.
PDB codes: 1een 1eeo
10820002 Y.A.Puius, E.V.Fedorov, L.Eichinger, M.Schleicher, and S.C.Almo (2000).
Mapping the functional surface of domain 2 in the gelsolin superfamily.
  Biochemistry, 39, 5322-5331.
PDB code: 1svy
9890920 H.Chen, L.N.Cong, Y.Li, Z.J.Yao, L.Wu, Z.Y.Zhang, T.R.Burke, and M.J.Quon (1999).
A phosphotyrosyl mimetic peptide reverses impairment of insulin-stimulated translocation of GLUT4 caused by overexpression of PTP1B in rat adipose cells.
  Biochemistry, 38, 384-389.  
15992069 J.L.Evans, and B.Jallal (1999).
Protein tyrosine phosphatases: their role in insulin action and potential as drug targets.
  Expert Opin Investig Drugs, 8, 139-160.  
10213634 N.R.Glover, and A.S.Tracey (1999).
Nuclear magnetic resonance and restrained molecular dynamics studies of the interaction of an epidermal growth factor-derived peptide with protein tyrosine phosphatase 1B.
  Biochemistry, 38, 5256-5271.  
9922143 M.R.Groves, Z.J.Yao, P.P.Roller, T.R.Burke, and D.Barford (1998).
Structural basis for inhibition of the protein tyrosine phosphatase 1B by phosphotyrosine peptide mimetics.
  Biochemistry, 37, 17773-17783.
PDB codes: 1bzc 1bzh 1bzj
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.