![]() Insulin binding to the insulin receptor activates downstream signaling that leads to the translocation of GLUT4 from the intracellular compartments to the plasma membrane where it performs glucose transport –. In the absence of insulin, the majority of GLUT4 expressed is confined to intracellular compartments. It is mainly expressed in adipocytes and muscle cells, and plays a major role in insulin-mediated blood glucose homeostasis. GLUT4 is a member of Class I subfamily and transports D-glucose across the membrane. Based on the substrate specificity, GLUT family is divided into 3 classes. The transport of glucose across the biological membrane is mediated by facilitative transporters called glucose transporters (GLUTs), which belong to the major facilitator superfamily (MFS), the largest family of secondary active transporters that utilize the solute gradient for the transport of substrates. These data are consistent with the biochemical studies, suggesting an inhibitory role for ATP in GLUT-mediated glucose transport. Various inter-domain hydrogen bonds and switching of a salt-bridge network from E345-R350-E409 to E345-R169-E409 contributed to this ATP-mediated channel constriction favoring substrate occlusion and prevention of its release into cytoplasm. Simulation studies suggested distinct conformational changes for the GLUT4 domains in the ATP substrate-bound form and favor a constricted behavior for the transport channel. ![]() Principal component analysis suggested a clockwise movement for the domains in the apo form, whereas ATP substrate-bound form induced an anti-clockwise rotation. Simulation studies with the substrate bound form proposed a stable state of GLUT4 with glucose, which can be a substrate-occluded state of the transporter. Apo form simulation analysis revealed an extracellular open conformation of GLUT4 in the membrane favoring easy exofacial binding of substrate. In the present study, the dynamic behavior of GLUT4 in a membrane environment was analyzed using three forms of GLUT4 (apo, substrate and ATP-substrate bound states). ![]()
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