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J. Biol. Chem., Vol. 281, Issue 9, 5797-5803, March 3, 2006

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Docking Studies Show That D-Glucose and Quercetin Slide through the Transporter GLUT1^*

Philip Cunningham, Iram Afzal-Ahmed¹, and Richard J. Naftalin²

From the Bioinformatics, Franklin-Wilkins Building, King's College London, London SE1 9NH, United Kingdom and Department of Physiology, King's College London, Guys' Campus, London SE1 1UL, United Kingdom

On a three-dimensional templated model of GLUT1 (Protein Data Bank code 1SUK), a molecular recognition program, AUTODOCK 3, reveals nine hexose-binding clusters spanning the entire "hydrophilic" channel. Five of these cluster sites are within 3-5 Å of 10 glucose transporter deficiency syndrome missense mutations. Another three sites are within 8 Å of two other missense mutations. D-Glucose binds to five sites in the external channel opening, with increasing affinity toward the pore center and then passes via a narrow channel into an internal vestibule containing four lower affinity sites. An external site, not adjacent to any mutation, also binding phloretin but recognizing neither D-fructose nor L-glucose, may be the main threading site for glucose uptake. Glucose exit from human erythrocytes is inhibited by quercetin (K_i = 2.4 µM) but not anionic quercetin-semiquinone. Quercetin influx is retarded by extracellular D-glucose (50 mM) but not by phloretin and accelerated by intracellular D-glucose. Quercetin docking sites are absent from the external opening but fill the entire pore center. In the inner vestibule, Glu²⁵⁴ and Lys²⁵⁶ hydrogen-bond quercetin (K_i 10 µM) but not quercetin-semiquinone. Consistent with the kinetics, this site also binds D-glucose, so quercetin displacement by glucose could accelerate quercetin influx, whereas quercetin binding here will competitively inhibit glucose efflux. -D-Hexoses dock twice as frequently as their -anomers to the 23 aromatic residues in the transport pathway, suggesting that endocyclic hexose hydrogens, as with maltosaccharides in maltoporins, form -bonds with aromatic rings and slide between sites instead of being translocated via a single alternating site.

Received for publication, August 25, 2005 , and in revised form, December 19, 2005.

^* 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 A British Heart Foundation research student.

² To whom correspondence should be addressed. Tel.: 44-207-848-6216; Fax: 44-207-848-6220; E-mail: richard.naftalin{at}kcl.ac.uk.

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