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Bridging the gap between structure and kinetics of human SGLT1
Monica Sala-Rabanal1, Bruce A Hirayama, Donald D F Loo
1Department of Physiology, The Geffen School of Medicine at University of California, Los Angeles, California 90095-1751, USA.
American Journal of Physiology. Cell Physiology
|December 14, 2011
Summary
The sodium-glucose cotransporter hSGLT1
Area of Science:
- Biochemistry
- Molecular Biology
- Structural Biology
Background:
- hSGLT1 is a Na(+)-glucose cotransporter crucial for solute transport.
- Structural studies reveal conserved folds among Na(+) transporters from different gene families.
Purpose of the Study:
- To elucidate the structure-function relationship of hSGLT1.
- To investigate the roles of conserved residues in hSGLT1's transport mechanism.
Main Methods:
- Homology modeling of hSGLT1 in two conformations.
- Site-directed mutagenesis of conserved residues.
- Functional characterization using biophysical and biochemical assays in Xenopus oocytes.
- Substituted-cysteine accessibility studies.
Main Results:
- Mutations in ligand binding sites significantly alter glucose affinity (K(0.5)).
- External gate mutations affect Na(+)-to-sugar stoichiometry, impacting cotransporter efficiency.
- F101C mutation specifically affects phlorizin binding, suggesting a shared binding site for glucose and phlorizin.
Conclusions:
- Glucose and phlorizin bind to the same site on hSGLT1.
- External Na(+) binding opens the sugar binding vestibule, which closes upon substrate binding.
- These findings bridge kinetic and structural insights into cotransporter function.
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