1PXH

Crystal structure of protein tyrosine phosphatase 1B with potent and selective bidentate inhibitor compound 2


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.15 Å
  • R-Value Free: 0.207 
  • R-Value Work: 0.200 
  • R-Value Observed: 0.203 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Crystal structure of PTP1B complexed with a potent and selective bidentate inhibitor.

Sun, J.P.Fedorov, A.A.Lee, S.Y.Guo, X.L.Shen, K.Lawrence, D.S.Almo, S.C.Zhang, Z.Y.

(2003) J Biol Chem 278: 12406-12414

  • DOI: https://doi.org/10.1074/jbc.M212491200
  • Primary Citation of Related Structures:  
    1PXH

  • PubMed Abstract: 

    Protein-tyrosine phosphatase 1B (PTP1B) has been implicated as an important regulator in several signaling pathways including those initiated by insulin and leptin. Potent and specific PTP1B inhibitors could serve as useful tools in elucidating the physiological functions of PTP1B and may constitute valuable therapeutics in the treatment of several human diseases. We have determined the crystal structure of PTP1B in complex with compound 2, the most potent and selective PTP1B inhibitor reported to date. The structure at 2.15-A resolution reveals that compound 2 simultaneously binds to the active site and a unique proximal noncatalytic site formed by Lys-41, Arg-47, and Asp-48. The structural data are further corroborated by results from kinetic analyses of the interactions of PTP1B and its site-directed mutants with compound 2 and several of its variants. Although many of the residues important for interactions between PTP1B and compound 2 are not unique to PTP1B, the combinations of all contact residues differ between PTP isozymes, which provide a structural basis for potent and selective PTP1B inhibition. Our data further suggest that potent, yet highly selective, PTP1B inhibitory agents can be acquired by targeting the area defined by residues Lys-41, Arg-47, and Asp-48, in addition to the previously identified second aryl phosphate-binding pocket.


  • Organizational Affiliation

    Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Protein-tyrosine phosphatase, non-receptor type 1321Homo sapiensMutation(s): 0 
Gene Names: ptp1b
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 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
SNA
Query on SNA

Download Ideal Coordinates CCD File 
D [auth A]N-{1-[5-(1-CARBAMOYL-2-MERCAPTO-ETHYLCARBAMOYL)-PENTYLCARBAMOYL]-2-[4-(DIFLUORO-PHOSPHONO-METHYL)-PHENYL]-ETHYL}-3-{2-[4-(DIFLUORO-PHOSPHONO-METHYL)-PHENYL]-ACETYLAMINO}-SUCCINAMIC ACID
C32 H41 F4 N5 O13 P2 S
JNKZDIBIDJQPGC-BOMBAVFCSA-N
ACY
Query on ACY

Download Ideal Coordinates CCD File 
E [auth A],
F [auth A]
ACETIC ACID
C2 H4 O2
QTBSBXVTEAMEQO-UHFFFAOYSA-N
MG
Query on MG

Download Ideal Coordinates CCD File 
B [auth A],
C [auth A]
MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
SNA PDBBind:  1PXH Ki: 1.8 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.15 Å
  • R-Value Free: 0.207 
  • R-Value Work: 0.200 
  • R-Value Observed: 0.203 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 52.84α = 90
b = 85.678β = 90
c = 88.678γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
CNSrefinement
CNSphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2003-08-12
    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: 2023-08-16
    Changes: Data collection, Database references, Derived calculations, Refinement description