8BWP

Cryo-EM structure of nanodisc-reconstituted wildtype human MRP4 (in complex with methotrexate)

Summary for 8BWP

• Entry DOI: 10.2210/pdb8bwp/pdb
• Related: 8BJF 8BWO
• EMDB information: 16088 16292 16293
• Descriptor: ATP-binding cassette sub-family C member 4, METHOTREXATE (2 entities in total)
• Functional Keywords: abc transporter, abcc4, mrp4, translocase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 150148.36

Authors

Raj, I.,Bloch, M.,Pape, T.H.,Taylor, N.M.I. (deposition date: 2022-12-07, release date: 2023-08-30, Last modification date: 2023-11-15)

Primary citation

Bloch, M.,Raj, I.,Pape, T.,Taylor, N.M.I.
Structural and mechanistic basis of substrate transport by the multidrug transporter MRP4.
Structure, 31:1407-1418.e6, 2023

PubMed Abstract: Multidrug resistance-associated protein 4 (MRP4) is an ATP-binding cassette (ABC) transporter expressed at multiple tissue barriers where it actively extrudes a wide variety of drug compounds. Overexpression of MRP4 provides resistance to clinically used antineoplastic agents, making it a highly attractive therapeutic target for countering multidrug resistance. Here, we report cryo-EM structures of multiple physiologically relevant states of lipid bilayer-embedded human MRP4, including complexes between MRP4 and two widely used chemotherapeutic agents and a complex between MRP4 and its native substrate. The structures display clear similarities and distinct differences in the coordination of these chemically diverse substrates and, in combination with functional and mutational analysis, reveal molecular details of the transport mechanism. Our study provides key insights into the unusually broad substrate specificity of MRP4 and constitutes an important contribution toward a general understanding of multidrug transporters.

PubMed: 37683641
DOI: 10.1016/j.str.2023.08.014

Experimental method

ELECTRON MICROSCOPY (3.6 Å)