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J Biol Chem. December 31, 2004; 279 (53): 55147-52.

A structural basis for the acute effects of HIV protease inhibitors on GLUT4 intrinsic activity.

Hertel J , Struthers H , Horj CB , Hruz PW .

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 mum. 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-[(125)I]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.

PubMed ID: 15496402
PMC ID: PMC1403823
Article link: J Biol Chem.
Grant support: AI 48747 NIAID NIH HHS , DK 064572 NIDDK NIH HHS , K08 AI049747-02 NIAID NIH HHS , K08 AI049747-03 NIAID NIH HHS , R01 DK064572-01 NIDDK NIH HHS , R01 DK064572-02 NIDDK NIH HHS , K08 AI049747 NIAID NIH HHS , R01 DK064572 NIDDK NIH HHS

Genes referenced: ins slc2a1 slc2a4

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