8IZ7

cryo-EM structure of sulindac-bound hMRP4

8IZ7 の概要

• エントリーDOI: 10.2210/pdb8iz7/pdb
• EMDBエントリー: 35834
• 分子名称: ATP-binding cassette sub-family C member 4, [(1Z)-5-fluoro-2-methyl-1-{4-[methylsulfinyl]benzylidene}-1H-inden-3-yl]acetic acid (2 entities in total)
• 機能のキーワード: cryo-em structure of sulindac-bound hmrp4, membrane protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 153527.77

構造登録者

Liu, Z.M.,Huang, Y. (登録日: 2023-04-06, 公開日: 2024-04-10, 最終更新日: 2024-10-23)

主引用文献

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

実験手法

ELECTRON MICROSCOPY (3.8 Å)