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J. Biol. Chem., Vol. 281, Issue 12, 8010-8015, March 24, 2006

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Conformation-assisted Inhibition of Protein-tyrosine Phosphatase-1B Elicits Inhibitor Selectivity over T-cell Protein-tyrosine Phosphatase^*

Ernest Asante-Appiah¹, Sangita Patel, Caroline Desponts², Jillian M. Taylor³, Cheuk Lau^¶, Claude Dufresne^¶, Michel Therien^¶, Rick Friesen^¶, Joseph W. Becker, Yves Leblanc^¶, Brian P. Kennedy, and Giovanna Scapin

From the Departments of Biochemistry and Molecular Biology and ^¶Medicinal Chemistry, Merck Frosst Center for Therapeutic Research, Pointe-Claire, Dorval, Quebec H9R 4P8, Canada and the Department of Medicinal Chemistry, Merck & Co., Inc., Rahway, New Jersey 07065

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.

Received for publication, November 2, 2005 , and in revised form, December 21, 2005.

The atomic coordinates and structure factors (code 2FJM and 2FJN) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

² Current address: H. Lee Moffitt Comprehensive Cancer Center and Research Inst., University of South Florida, Tampa, FL 33612.

³ Current address: Dalhousie Medical School, Sir Charles Tupper Medical Building, 5849 University Avenue, Halifax, Nova Scotia B3H 4H7, Canada.

¹ To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, Merck Frosst Center for Therapeutic Research, P. O. Box 1005, Pointe-Claire, Dorval, Quebec H9R 4P8, Canada. Tel.: 514-428-3452; Fax: 514-428-4900; E-mail: ernest_asanteappiah{at}merck.com.

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