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Inhibition and transport mechanisms of the ABC transporter hMRP5
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Inhibition and transport mechanisms of the ABC transporter hMRP5
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Journal Article
Inhibition and transport mechanisms of the ABC transporter hMRP5
2024
Overview
Human multidrug resistance protein 5 (hMRP5) effluxes anticancer and antivirus drugs, driving multidrug resistance. To uncover the mechanism of hMRP5, we determine six distinct cryo-EM structures, revealing an autoinhibitory N-terminal peptide that must dissociate to permit subsequent substrate recruitment. Guided by these molecular insights, we design an inhibitory peptide that could block substrate entry into the transport pathway. We also identify a regulatory motif, comprising a positively charged cluster and hydrophobic patches, within the first nucleotide-binding domain that modulates hMRP5 localization by engaging with membranes. By integrating our structural, biochemical, computational, and cell biological findings, we propose a model for hMRP5 conformational cycling and localization. Overall, this work provides mechanistic understanding of hMRP5 function, while informing future selective hMRP5 inhibitor development. More broadly, this study advances our understanding of the structural dynamics and inhibition of ABC transporters.
Human multidrug resistance protein 5 (hMRP5) effluxes anticancer and antivirus drugs, driving multidrug resistance. Here, the authors present cryo-EM structures of hMRP5 in different states, showing that hMRP5 can be autoinhibited by a short peptide from its N-terminal tail, which prevents the entry of substrates into hMRP5’s transport pathway.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ ATP-Binding Cassette Transporters - chemistry
/ ATP-Binding Cassette Transporters - metabolism
/ Cancer
/ Humanities and Social Sciences
/ Humans
/ Multidrug Resistance-Associated Proteins - antagonists & inhibitors
/ Multidrug Resistance-Associated Proteins - chemistry
/ Multidrug Resistance-Associated Proteins - genetics
/ Multidrug Resistance-Associated Proteins - metabolism
/ Peptides
/ Proteins
/ Science
