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Conformation-assisted inhibition of protein-tyrosine phosphatase-1B elicits inhibitor selectivity over T-cell protein-tyrosine phosphatase.

Publication ,  Journal Article
Asante-Appiah, E; Patel, S; Desponts, C; Taylor, JM; Lau, C; Dufresne, C; Therien, M; Friesen, R; Becker, JW; Leblanc, Y; Kennedy, BP; Scapin, G
Published in: The Journal of biological chemistry
March 2006

PTP-1B represents an attractive target for the treatment of type 2 diabetes and obesity. Given the role that protein phosphatases play in the regulation of many biologically relevant processes, inhibitors against PTP-1B must be not only potent, but also selective. It has been extremely difficult to synthesize inhibitors that are selective over the highly homologous TCPTP. We have successfully exploited the conservative Leu119 to Val substitution between the two enzymes to synthesize a PTP-1B inhibitor that is an order of magnitude more selective over TCPTP. Structural analyses of PTP-1B/inhibitor complexes show a conformation-assisted inhibition mechanism as the basis for selectivity. Such an inhibitory mechanism may be applicable to other homologous enzymes.

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Published In

The Journal of biological chemistry

DOI

EISSN

1083-351X

ISSN

0021-9258

Publication Date

March 2006

Volume

281

Issue

12

Start / End Page

8010 / 8015

Related Subject Headings

  • Valine
  • Recombinant Proteins
  • Protein Tyrosine Phosphatases
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • Protein Conformation
  • Protein Binding
  • Mutation
  • Mutagenesis, Site-Directed
  • Mutagenesis
  • Molecular Conformation
 

Citation

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Asante-Appiah, E., Patel, S., Desponts, C., Taylor, J. M., Lau, C., Dufresne, C., … Scapin, G. (2006). Conformation-assisted inhibition of protein-tyrosine phosphatase-1B elicits inhibitor selectivity over T-cell protein-tyrosine phosphatase. The Journal of Biological Chemistry, 281(12), 8010–8015. https://doi.org/10.1074/jbc.m511827200
Asante-Appiah, Ernest, Sangita Patel, Caroline Desponts, Jillian M. Taylor, Cheuk Lau, Claude Dufresne, Michel Therien, et al. “Conformation-assisted inhibition of protein-tyrosine phosphatase-1B elicits inhibitor selectivity over T-cell protein-tyrosine phosphatase.The Journal of Biological Chemistry 281, no. 12 (March 2006): 8010–15. https://doi.org/10.1074/jbc.m511827200.
Asante-Appiah E, Patel S, Desponts C, Taylor JM, Lau C, Dufresne C, et al. Conformation-assisted inhibition of protein-tyrosine phosphatase-1B elicits inhibitor selectivity over T-cell protein-tyrosine phosphatase. The Journal of biological chemistry. 2006 Mar;281(12):8010–5.
Asante-Appiah, Ernest, et al. “Conformation-assisted inhibition of protein-tyrosine phosphatase-1B elicits inhibitor selectivity over T-cell protein-tyrosine phosphatase.The Journal of Biological Chemistry, vol. 281, no. 12, Mar. 2006, pp. 8010–15. Epmc, doi:10.1074/jbc.m511827200.
Asante-Appiah E, Patel S, Desponts C, Taylor JM, Lau C, Dufresne C, Therien M, Friesen R, Becker JW, Leblanc Y, Kennedy BP, Scapin G. Conformation-assisted inhibition of protein-tyrosine phosphatase-1B elicits inhibitor selectivity over T-cell protein-tyrosine phosphatase. The Journal of biological chemistry. 2006 Mar;281(12):8010–8015.

Published In

The Journal of biological chemistry

DOI

EISSN

1083-351X

ISSN

0021-9258

Publication Date

March 2006

Volume

281

Issue

12

Start / End Page

8010 / 8015

Related Subject Headings

  • Valine
  • Recombinant Proteins
  • Protein Tyrosine Phosphatases
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • Protein Conformation
  • Protein Binding
  • Mutation
  • Mutagenesis, Site-Directed
  • Mutagenesis
  • Molecular Conformation