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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • 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 Date

  • March 2006

Published In

Volume / Issue

  • 281 / 12

Start / End Page

  • 8010 - 8015

PubMed ID

  • 16407290

Electronic International Standard Serial Number (EISSN)

  • 1083-351X

International Standard Serial Number (ISSN)

  • 0021-9258

Digital Object Identifier (DOI)

  • 10.1074/jbc.m511827200


  • eng