Abstract
The human ATP-binding cassette transporter ABCG2 is a key to anticancer resistance and physiological detoxification. However, the molecular mechanism of substrate transport remains enigmatic. A hydrophobic di-leucine motif in the ABCG2 core separates a large intracellular cavity from a smaller upper cavity. We show that the di-leucine motif acts as a valve that controls drug extrusion. Moreover, the extracellular structure engages the re-entry helix and all extracellular loops to form a roof architecture on top of the upper cavity. Disulfide bridges and a salt bridge limit roof flexibility, but provide a lid-like function to control drug release. We propose that drug translocation from the central to the upper cavities through the valve is driven by a squeezing motion, suggesting that ABCG2 operates similar to a peristaltic pump. Finally, the roof contains essential residues, offering therapeutic options to block ABCG2 by either targeting the valve or essential residues in the roof.
Highlights
The human ATP-binding cassette transporter ABCG2 is a key to anticancer resistance and physiological detoxification
Cryo-electron microscopy structures of human ABCG2 revealed the first structure of human ABCG214, with structural coordinates that are almost identical to the ABCG5/G8 crystal structure[13]
We used the structural coordinates from all known Cryo-electron microscopy (cryo-EM) particle structures of ABCG214,19,20 and our own model[18], to generate a refined structure of human ABCG2, emphasizing on the roof architecture (Supplementary Fig. 1)
Summary
The human ATP-binding cassette transporter ABCG2 is a key to anticancer resistance and physiological detoxification. Mammalian ABCG family members share high evolutionary conservation with the fungal pleiotropic drug resistance (PDR) transporters, suggesting that they may utilize related mechanisms for substrate transport, including the coupling of the catalytic cycle with drug release[10,11]. ABCG5/G8 resembles an importer rather than an exporter, with a central cavity, a unique assembly of putative transmembrane helices, and the polar relay[12,13] Prominent elements at both membrane interfaces include the elbow helix at the inner membrane leaflet, and the re-entry helix embedded in the outer membrane leaflet, respectively[13]. Several independent reports model and predict essentially identical atomic structures of ABCG2, and suggest a conserved, but new fold adopted by the ABCG transporter family[15,16,17]. ABCG5/G8 and ABCG2 implies related transport mechanisms, suggesting that subfamily-specific catalytic cycles may exist[20,21,22,23]
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