Molecular basis of ligand recognition and transport by glucose transporters

• Autores: Dong Deng, Pengcheng Sun, Chuangye Yan, Meng Ke, Xin Jiang, Lei Xiong, Wenlin Ren, Kunio Hirata, Masaki Yamamoto, Shilong Fan, Nieng Yan
• Localización: Nature: International weekly journal of science, ISSN 0028-0836, Vol. 526, Nº 7573, 2015, págs. 391-396
• Idioma: inglés
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• Resumen

  • The major facilitator superfamily glucose transporters, exemplified by human GLUT1–4, have been central to the study of solute transport. Using lipidic cubic phase crystallization and microfocus X-ray diffraction, we determined the structure of human GLUT3 in complex with D-glucose at 1.5 Å resolution in an outward-occluded conformation. The high-resolution structure allows discrimination of both [alpha]- and [beta]-anomers of D-glucose. Two additional structures of GLUT3 bound to the exofacial inhibitor maltose were obtained at 2.6 Å in the outward-open and 2.4 Å in the outward-occluded states. In all three structures, the ligands are predominantly coordinated by polar residues from the carboxy terminal domain. Conformational transition from outward-open to outward-occluded entails a prominent local rearrangement of the extracellular part of transmembrane segment TM7. Comparison of the outward-facing GLUT3 structures with the inward-open GLUT1 provides insights into the alternating access cycle for GLUTs, whereby the C-terminal domain provides the primary substrate-binding site and the amino-terminal domain undergoes rigid-body rotation with respect to the C-terminal domain. Our studies provide an important framework for the mechanistic and kinetic understanding of GLUTs and shed light on structure-guided ligand design.