1NWL

Crystal structure of the PTP1B complexed with SP7343-SP7964, a pTyr mimetic


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.245 
  • R-Value Work: 0.208 
  • R-Value Observed: 0.210 

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Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Discovery of a New Phosphotyrosine Mimetic for PTP1B Using Breakaway Tethering

Erlanson, D.A.McDowell, R.S.He, M.M.Randal, M.Simmons, R.L.Kung, J.Waight, A.Hansen, S.

(2003) J Am Chem Soc 125: 5602-5603

  • DOI: https://doi.org/10.1021/ja034440c
  • Primary Citation of Related Structures:  
    1NWE, 1NWL

  • PubMed Abstract: 

    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.


  • Organizational Affiliation

    Sunesis Pharmaceuticals, Inc., 341 Oyster Point Boulevard, South San Francisco, California 94080, USA. erlanson@sunesis.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
protein-tyrosine phosphatase, non-receptor type 1298Homo sapiensMutation(s): 3 
Gene Names: PTPN1
EC: 3.1.3.48
UniProt & NIH Common Fund Data Resources
Find proteins for P18031 (Homo sapiens)
Explore P18031 
Go to UniProtKB:  P18031
PHAROS:  P18031
GTEx:  ENSG00000196396 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP18031
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
964
Query on 964

Download Ideal Coordinates CCD File 
C [auth A]3-(4-{2-[2-(2-BROMO-ACETYLAMINO)-ETHYLDISULFANYL]-ETHYLCARBAMOYL}-CYCLOHEXYLCARBAMOYL)-PYRAZINE-2-CARBOXYLIC ACID
C19 H27 N5 O5 S2
OMSKFAYIWROESZ-OKILXGFUSA-N
MG
Query on MG

Download Ideal Coordinates CCD File 
B [auth A]MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
964 PDBBind:  1NWL Ki: 4.10e+6 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.245 
  • R-Value Work: 0.208 
  • R-Value Observed: 0.210 
  • Space Group: P 31 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 88.721α = 90
b = 88.721β = 90
c = 104.998γ = 120
Software Package:
Software NamePurpose
MOSFLMdata reduction
SCALAdata scaling
AMoREphasing
REFMACrefinement
CCP4data scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2003-04-01
    Type: Initial release
  • Version 1.1: 2008-04-29
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2021-10-27
    Changes: Database references, Derived calculations
  • Version 1.4: 2024-02-14
    Changes: Data collection