8WI0

wt-hMRP5 inward-open

Summary for 8WI0

• Entry DOI: 10.2210/pdb8wi0/pdb
• EMDB information: 37554
• Descriptor: ATP-binding cassette sub-family C member 5 (2 entities in total)
• Functional Keywords: wt-hmrp5 inward-open, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 162865.79

Authors

Liu, Z.M.,Huang, Y. (deposition date: 2023-09-24, release date: 2024-07-03)

Primary citation

Huang, Y.,Xue, C.,Bu, R.,Wu, C.,Li, J.,Zhang, J.,Chen, J.,Shi, Z.,Chen, Y.,Wang, Y.,Liu, Z.
Inhibition and transport mechanisms of the ABC transporter hMRP5.
Nat Commun, 15:4811-4811, 2024

PubMed 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.

PubMed: 38844452
DOI: 10.1038/s41467-024-49204-1

Experimental method

ELECTRON MICROSCOPY (2.93 Å)