9BUK

Outward-facing, ATP-bound Multidrug Resistance-associated Protein 2 (MRP2) (E1462Q)

Summary for 9BUK

• Entry DOI: 10.2210/pdb9buk/pdb
• Related: 9BR2
• EMDB information: 44833 44911
• Descriptor: ATP-binding cassette sub-family C member 2, ADENOSINE-5'-TRIPHOSPHATE, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: abc transporter, multidrug resistance, regulatory domain, nucleotide binding, transport protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 179758.04

Authors

Koide, E.,Chen, J. (deposition date: 2024-05-17, release date: 2024-12-18, Last modification date: 2025-02-12)

Primary citation

Koide, E.,Pietz, H.L.,Beltran, J.,Chen, J.
Structural basis for the transport and regulation mechanism of the multidrug resistance-associated protein 2.
Nat Commun, 16:484-484, 2025

PubMed Abstract: Multidrug resistance-associated protein 2 (MRP2) is an ATP-powered exporter important for maintaining liver homeostasis and a potential contributor to chemotherapeutic resistance. Using cryogenic electron microscopy (cryo-EM), we determine the structures of human MRP2 in three conformational states: an autoinhibited state, a substrate-bound pre-translocation state, and an ATP-bound post-translocation state. In the autoinhibited state, the cytosolic regulatory (R) domain plugs into the transmembrane substrate-binding site and extends into the cytosol to form a composite ATP-binding site at the surface of nucleotide-binding domain 2. Substrate displaces the R domain, permitting conformational changes necessary for transport. These observations suggest that the R domain functions as a selectivity gauge, where only at sufficiently high concentrations can the substrate effectively initiate transport. Comparative structural analyzes of MRP2 bound to various substrates, as determined in this study and others, reveal how MRP2 recognizes a diverse array of compounds, supporting its role in multidrug resistance.

PubMed: 39779684
DOI: 10.1038/s41467-024-55810-w

Experimental method

ELECTRON MICROSCOPY (3.4 Å)