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J. Biol. Chem., Vol. 279, Issue 53, 55147-55152, December 31, 2004

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A Structural Basis for the Acute Effects of HIV Protease Inhibitors on GLUT4 Intrinsic Activity^*

Johann Hertel, Heidi Struthers, Christal Baird Horj, and Paul W. Hruz¶

From the Department of Pediatrics and the Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110

Human immunodeficiency virus (HIV) protease inhibitors (PIs) act as reversible noncompetitive inhibitors of GLUT4 with binding affinities in the low micromolar range and are known to contribute to alterations in glucose homeostasis during treatment of HIV infection. As aspartyl protease inhibitors, these compounds all possess a core peptidomimetic structure together with flanking hydrophobic moieties. To determine the molecular basis for GLUT4 inhibition, a family of related oligopeptides containing structural elements found in PIs was screened for their ability to inhibit 2-deoxyglucose transport in primary rat adipocytes. The peptide oxybenzylcarbonyl-His-Phe-Phe-O-ethyl ester (zHFFe) was identified as a potent inhibitor of zero-trans glucose flux with a K_i of 26 µM. Similar to PIs, transport inhibition by this peptide was acute, noncompetitive, and reversible. Within a Xenopus oocyte expression system, zHFFe acutely and reversibly inhibited GLUT4-mediated glucose uptake, whereas GLUT1 activity was unaffected at concentrations as high as 1 mM. The related photoactivatable peptide zHFF-p-benzoylphenylalanine-[¹²⁵I]Tyr-O-ethyl ester selectively labeled GLUT4 in rat adipocytes and indinavir effectively protected against photolabeling. Furthermore, GLUT4 bound to a peptide affinity column containing the zHFF sequence and was eluted by indinavir. These data establish a structural basis for PI effects on GLUT4 activity and support the direct binding of PIs to the transport protein as the mechanism for acute inhibition of insulin-stimulated glucose uptake.

Received for publication, September 20, 2004 , and in revised form, October 19, 2004.

^* This research was supported by Grants AI 49747 and DK064572 from the National Institutes of Health, the American Diabetes Association, and by the Diabetes Research Training Center at Washington University School of Medicine. 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.

^¶ To whom correspondence should be addressed: Washington University School of Medicine, 660 S. Euclid Ave., Campus Box 8208, St. Louis, MO 63110. Tel.: 314-286-2797; Fax: 314-286-2892; E-mail: hruz_p{at}kids.wustl.edu.

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