8IZ9

cryo-EM structure of PGE1-bound hMRP4

Summary for 8IZ9

• Entry DOI: 10.2210/pdb8iz9/pdb
• EMDB information: 35836
• Descriptor: ATP-binding cassette sub-family C member 4, 7-[(1R,3R)-3-hydroxy-2-[(1E,3S)-3-hydroxyoct-1-en-1-yl]-5-oxocyclopentyl]heptanoic acid (2 entities in total)
• Functional Keywords: cryo-em structure of pge1-bound hmrp4, membrane protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 153525.84

Authors

Liu, Z.M.,Huang, Y. (deposition date: 2023-04-06, release date: 2024-04-10, Last modification date: 2024-10-23)

Primary citation

Huang, Y.,Xue, C.,Wang, L.,Bu, R.,Mu, J.,Wang, Y.,Liu, Z.
Structural basis for substrate and inhibitor recognition of human multidrug transporter MRP4.
Commun Biol, 6:549-549, 2023

PubMed Abstract: Human multidrug resistance protein 4 (hMRP4, also known as ABCC4), with a representative topology of the MRP subfamily, translocates various substrates across the membrane and contributes to the development of multidrug resistance. However, the underlying transport mechanism of hMRP4 remains unclear due to a lack of high-resolution structures. Here, we use cryogenic electron microscopy (cryo-EM) to resolve its near-atomic structures in the apo inward-open and the ATP-bound outward-open states. We also capture the PGE1 substrate-bound structure and, importantly, the inhibitor-bound structure of hMRP4 in complex with sulindac, revealing that substrate and inhibitor compete for the same hydrophobic binding pocket although with different binding modes. Moreover, our cryo-EM structures, together with molecular dynamics simulations and biochemical assay, shed light on the structural basis of the substrate transport and inhibition mechanism, with implications for the development of hMRP4-targeted drugs.

PubMed: 37217525
DOI: 10.1038/s42003-023-04935-7

Experimental method

ELECTRON MICROSCOPY (2.95 Å)