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P-glycoprotein (Pgp) is a prototypical ATP-binding cassette (ABC) transporter of great biological and clinical significance.Pgp confers cancer multidrug resistance and mediates the bioavailability and pharmacokinetics of many drugs (Juliano and Ling, 1976; Ueda et al., 1986; Sharom, 2011). Decades of structural and biochemical studies have provided insights into how Pgp binds diverse compounds (Loo and Clarke, 2000; Loo et al., 2009; Aller et al., 2009; Alam et al., 2019; Nosol et al., 2020; Chufan et al., 2015), but how they are translocated through the membrane has remained elusive. Here, we covalently attached a cyclic substrate to discrete sites of Pgp and determined multiple complex structures in inward- and outward-facing states by cryoEM. In conjunction with molecular dynamics simulations, our structures trace the substrate passage across the membrane and identify conformational changes in transmembrane helix 1 (TM1) as regulators of substrate transport. In mid-transport conformations, TM1 breaks at glycine 72. Mutation of this residue significantly impairs drug transport of Pgp in vivo, corroborating the importance of its regulatory role. Importantly, our data suggest that the cyclic substrate can exit Pgp without the requirement of a wide-open outward-facing conformation, diverting from the common efflux model for Pgp and other ABC exporters. The substrate transport mechanism of Pgp revealed here pinpoints critical targets for future drug discovery studies of this medically relevant system.more » « less
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A novel high gain full duplex flexible antenna using PET paper and foam is presented for 5.8 GHz. Two rectangular patches are placed on top layer whereas bottom layer has defected ground structure printed on it. Patches are fed with inset line feeding. This antenna works effectively from 5.75GHz to 5.81 GHz for full duplex purpose while maintaining a radiation efficiency of 98.6% and peak gain of 8.78 dB at 5.8 GHz. This antenna is believed to be first proposed antenna which is flexible and full duplex with such high gain while working at 5.8 GHz. It also has simple structure, low cost, light weight along with good isolation and gain, which eventually makes it a good candidate for 5.8 GHz full duplex applications.more » « less
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