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The structural basis for the selectivity of benzotriazole inhibitors of PTP1B.

Publication ,  Journal Article
Scapin, G; Patel, SB; Becker, JW; Wang, Q; Desponts, C; Waddleton, D; Skorey, K; Cromlish, W; Bayly, C; Therien, M; Gauthier, JY; Li, CS ...
Published in: Biochemistry
October 2003

Protein tyrosine phosphatase 1B (PTP1B) has been implicated in the regulation of the insulin signaling pathway and represents an attractive target for the design of inhibitors in the treatment of type 2 diabetes and obesity. Inspection of the structure of PTP1B indicates that potent PTP1B inhibitors may be obtained by targeting a secondary aryl phosphate-binding site as well as the catalytic site. We report here the crystal structures of PTP1B in complex with first and second generation aryldifluoromethyl-phosphonic acid inhibitors. While all compounds bind in a previously unexploited binding pocket near the primary binding site, the second generation compounds also reach into the secondary binding site, and exhibit moderate selectivity for PTP1B over the closely related T-cell phosphatase. The molecular basis for the selectivity has been confirmed by single point mutation at position 52, where the two phosphatases differ by a phenylalanine-to-tyrosine switch. These compounds present a novel platform for the development of potent and selective PTP1B inhibitors.

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Published In

Biochemistry

DOI

EISSN

1520-4995

ISSN

0006-2960

Publication Date

October 2003

Volume

42

Issue

39

Start / End Page

11451 / 11459

Related Subject Headings

  • Triazoles
  • Substrate Specificity
  • Structure-Activity Relationship
  • Recombinant Proteins
  • Protein Tyrosine Phosphatases
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • Point Mutation
  • Phosphinic Acids
  • Models, Molecular
  • Inhibitory Concentration 50
 

Citation

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Scapin, G., Patel, S. B., Becker, J. W., Wang, Q., Desponts, C., Waddleton, D., … Asante-Appiah, E. (2003). The structural basis for the selectivity of benzotriazole inhibitors of PTP1B. Biochemistry, 42(39), 11451–11459. https://doi.org/10.1021/bi035098j
Scapin, Giovanna, Sangita B. Patel, Joseph W. Becker, Qingping Wang, Caroline Desponts, Deena Waddleton, Kathryn Skorey, et al. “The structural basis for the selectivity of benzotriazole inhibitors of PTP1B.Biochemistry 42, no. 39 (October 2003): 11451–59. https://doi.org/10.1021/bi035098j.
Scapin G, Patel SB, Becker JW, Wang Q, Desponts C, Waddleton D, et al. The structural basis for the selectivity of benzotriazole inhibitors of PTP1B. Biochemistry. 2003 Oct;42(39):11451–9.
Scapin, Giovanna, et al. “The structural basis for the selectivity of benzotriazole inhibitors of PTP1B.Biochemistry, vol. 42, no. 39, Oct. 2003, pp. 11451–59. Epmc, doi:10.1021/bi035098j.
Scapin G, Patel SB, Becker JW, Wang Q, Desponts C, Waddleton D, Skorey K, Cromlish W, Bayly C, Therien M, Gauthier JY, Li CS, Lau CK, Ramachandran C, Kennedy BP, Asante-Appiah E. The structural basis for the selectivity of benzotriazole inhibitors of PTP1B. Biochemistry. 2003 Oct;42(39):11451–11459.
Journal cover image

Published In

Biochemistry

DOI

EISSN

1520-4995

ISSN

0006-2960

Publication Date

October 2003

Volume

42

Issue

39

Start / End Page

11451 / 11459

Related Subject Headings

  • Triazoles
  • Substrate Specificity
  • Structure-Activity Relationship
  • Recombinant Proteins
  • Protein Tyrosine Phosphatases
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • Point Mutation
  • Phosphinic Acids
  • Models, Molecular
  • Inhibitory Concentration 50