EMD-37554

Single-particle
2.93 Å
EMD-37554 Deposition: 24/09/2023
Map released: 03/07/2024
Last modified: 20/11/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links

EMD-37554

wt-hMRP5 inward-open

EMD-37554

Single-particle
2.93 Å
EMD-37554 Deposition: 24/09/2023
Map released: 03/07/2024
Last modified: 20/11/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Sample Organism: Homo sapiens
Sample: wt-hMRP5
Fitted models: 8wi0 (Avg. Q-score: 0.482)

Deposition Authors: Liu ZM, Huang Y
Inhibition and transport mechanisms of the ABC transporter hMRP5.
Huang Y, Xue C , Bu R, Wu C , Li J, Zhang J , Chen J, Shi Z, Chen Y , Wang Y , Liu Z
(2024) Nat Commun , 15 , 4811 - 4811
PUBMED: 38844452
DOI: doi:10.1038/s41467-024-49204-1
ISSN: 2041-1723
Abstract:
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.