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J. Biol. Chem., Vol. 282, Issue 5, 2911-2917, February 2, 2007

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The Role of the C-terminal Domain of Protein Tyrosine Phosphatase-1B in Phosphatase Activity and Substrate Binding^*

From the Metabolic and Cardiovascular Diseases Research, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts 02139

Protein tyrosine phosphatase 1B (PTP-1B) has been implicated in the regulation of the insulin receptor. Dephosphorylation of the insulin receptor results in decreased insulin signaling and thus decreased glucose uptake. PTP-1B^–/– mice have increased insulin sensitivity and are resistant to weight gain when fed a high fat diet, validating PTP-1B as a potential target for the treatment of type 2 diabetes. Many groups throughout the world have been searching for selective inhibitors for PTP-1B, and most of them target inhibitors to PTP-1B-(1–298), the N-terminal catalytic domain of the enzyme. However, the C-terminal domain is quite large and could influence the activity of the enzyme. Using two constructs of PTP-1B and a phosphopeptide as substrate, steady state assays showed that the presence of the C-terminal domain decreased both the K_m and the k_cat 2-fold. Pre-steady state kinetic experiments showed that the presence of the C-terminal domain improved the affinity of the enzyme for a phosphopeptide 2-fold, primarily because the off-rate was slower. This suggests that the C-terminal domain of PTP-1B may contact the phosphopeptide in some manner, allowing it to remain at the active site longer. This could be useful when screening libraries of compounds for inhibitors of PTP-1B. A compound that is able to make contacts with the C-terminal domain of PTP-1B would not only have a modest improvement in affinity but may also provide for specificity over other phosphatases.

Received for publication, October 27, 2006

^* 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.

¹ To whom correspondence should be addressed: Intra-Cellular Therapies, Inc. (ITI), Audubon Biomedical Science and Technology Park, 3960 Broadway, NY, NY 10032. Tel.: 212-923-3344 (ext. 210); Fax: 212-923-3388; E-mail: lwennogle{at}intracellulartherapies.com.

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