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ABCG2, an essential ATP-binding cassette transporter, plays a pivotal role in the efflux of numerous chemical toxins across the cellular membrane, thus affecting their absorption, distribution, and excretion in the body. In particular, ABCG2 is known to significantly impact the effectiveness of various chemotherapeutic agents. Here we explore the molecular properties of ABCG2 by investigating a newly identified tumor-derived, somatic mutation, ABCG2-Q393K. Intriguingly, despite the intact interactions of the Q393K mutant with substrates and nucleotides, it cannot transport any tested substrates. Our structural modeling and molecular dynamics simulations, rooted in cryo-EM structures of ABCG2, unveiled that the Q393K substitution establishes a robust salt-bridge interaction with residue E446. We suggest that this salt bridge, formed at the interface between the transmembrane and nucleotide-binding domains …