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

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
Biochemistry 42 11451-9 (2003)
Related entries: 1q6m, 1q6n, 1q6p, 1q6s, 1q6t

Cited: 51 times
EuropePMC logo PMID: 14516196

Abstract

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.

Articles - 1q6j mentioned but not cited (2)

  1. Knowledge-based characterization of similarity relationships in the human protein-tyrosine phosphatase family for rational inhibitor design. Vidović D, Schürer SC. J Med Chem 52 6649-6659 (2009)
  2. research-article Native dynamics and allosteric responses in PTP1B probed by high-resolution HDX-MS. Woods VA, Abzalimov RR, Keedy DA. bioRxiv 2023.07.12.548582 (2023)


Reviews citing this publication (7)

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