PDBsum entry 1nwe

Go to PDB code: 
protein ligands links
Hydrolase PDB id
Protein chain
296 a.a. *
* Residue conservation analysis
PDB id:
Name: Hydrolase
Title: Ptp1b r47c modified at c47 with n-[4-(2-{2-[3-(2-bromo- acetylamino)-propionylamino]-3-hydroxy-propionylamino}- ethyl)-phenyl]-oxalamic acid
Structure: Protein-tyrosine phosphatase, non-receptor type 1. Chain: a. Fragment: catalytic domain, residues 1-298. Synonym: protein-tyrosine phosphatase 1b, ptp-1b. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: ptpn1. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693.
3.10Å     R-factor:   0.284     R-free:   0.305
Authors: D.A.Erlanson,R.S.Mcdowell,M.M.He,M.Randal,R.L.Simmons, J.Kung,A.Waight,S.K.Hansen
Key ref: D.A.Erlanson et al. (2003). Discovery of a new phosphotyrosine mimetic for PTP1B using breakaway tethering. J Am Chem Soc, 125, 5602-5603. PubMed id: 12733877 DOI: 10.1021/ja034440c
06-Feb-03     Release date:   06-May-03    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P18031  (PTN1_HUMAN) -  Tyrosine-protein phosphatase non-receptor type 1
435 a.a.
296 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 3 residue positions (black crosses)

 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: 10.1021/ja034440c J Am Chem Soc 125:5602-5603 (2003)
PubMed id: 12733877  
Discovery of a new phosphotyrosine mimetic for PTP1B using breakaway tethering.
D.A.Erlanson, R.S.McDowell, M.M.He, M.Randal, R.L.Simmons, J.Kung, A.Waight, S.K.Hansen.
Protein tyrosine phosphatases play important roles in many signaling cascades involved in human disease. The identification of druglike inhibitors for these targets is a major challenge, and the discovery of suitable phosphotyrosine (pY) mimetics remains one of the key difficulties. Here we describe an extension of tethering technology, "breakaway tethering", which is ideally suited for discovering such new chemical entities. The approach involves first irreversibly modifying a protein with an extender that contains both a masked thiol and a known pY mimetic. The extender is then cleaved to release the pY mimetic, unmasking the thiol. The resulting protein is screened against a library of disulfide-containing small molecule fragments; any molecules with inherent affinity for the pY binding site will preferentially form disulfides with the extender, allowing for their identification by mass spectrometry. The ability to start from a known substrate mimimizes perturbation of protein structure and increases the opportunity to probe the active site using tethering. We applied this approach to the anti-diabetic protein PTP1B to discover a pY mimetic which belongs to a new molecular class and which binds in a novel fashion.

Literature references that cite this PDB file's key reference

  PubMed id Reference
  21506176 J.Schulze Wischeler, D.Sun, N.U.Sandner, U.Linne, A.Heine, U.Koert, and G.Klebe (2011).
Stereo- and Regioselective Azide/Alkyne Cycloadditions in Carbonic Anhydrase II via Tethering, Monitored by Crystallography and Mass Spectrometry.
  Chemistry, 17, 5842-5851.
PDB codes: 3kig 3kne
21420867 V.V.Vintonyak, H.Waldmann, and D.Rauh (2011).
Using small molecules to target protein phosphatases.
  Bioorg Med Chem, 19, 2145-2155.  
19410499 V.V.Vintonyak, A.P.Antonchick, D.Rauh, and H.Waldmann (2009).
The therapeutic potential of phosphatase inhibitors.
  Curr Opin Chem Biol, 13, 272-283.  
17444517 G.Tóth, K.Mukhyala, and J.A.Wells (2007).
Computational approach to site-directed ligand discovery.
  Proteins, 68, 551-560.  
16407290 E.Asante-Appiah, S.Patel, C.Desponts, J.M.Taylor, C.Lau, C.Dufresne, M.Therien, R.Friesen, J.W.Becker, Y.Leblanc, B.P.Kennedy, and G.Scapin (2006).
Conformation-assisted inhibition of protein-tyrosine phosphatase-1B elicits inhibitor selectivity over T-cell protein-tyrosine phosphatase.
  J Biol Chem, 281, 8010-8015.
PDB codes: 2fjm 2fjn
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
15139811 D.A.Erlanson, J.A.Wells, and A.C.Braisted (2004).
Tethering: fragment-based drug discovery.
  Annu Rev Biophys Biomol Struct, 33, 199-223.  
15288250 D.A.Erlanson, and S.K.Hansen (2004).
Making drugs on proteins: site-directed ligand discovery for fragment-based lead assembly.
  Curr Opin Chem Biol, 8, 399-406.  
15314233 J.A.Hardy, J.Lam, J.T.Nguyen, T.O'Brien, and J.A.Wells (2004).
Discovery of an allosteric site in the caspases.
  Proc Natl Acad Sci U S A, 101, 12461-12466.
PDB codes: 1shj 1shl
15300826 T.Berg (2004).
Use of "tethering" for the identification of a small molecule that binds to a dynamic hot spot on the interleukin-2 surface.
  Chembiochem, 5, 1051-1053.  
12850324 M.Brown (2003).
A tale of two necessities: breakaway technology versus diabetes.
  Drug Discov Today, 8, 561-562.  
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.