Structural and mechanistic basis of substrate transport by the multidrug transporter MRP4

Research output: Contribution to journal › Journal article › Research › peer-review

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Structural and mechanistic basis of substrate transport by the multidrug transporter MRP4. / Bloch, Magnus; Raj, Isha; Pape, Tillmann; Taylor, Nicholas M.I.

In: Structure, Vol. 31, No. 11, 2023, p. 1407-1418.e6.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Bloch, M, Raj, I, Pape, T & Taylor, NMI 2023, 'Structural and mechanistic basis of substrate transport by the multidrug transporter MRP4', Structure, vol. 31, no. 11, pp. 1407-1418.e6. https://doi.org/10.1016/j.str.2023.08.014

APA

Bloch, M., Raj, I., Pape, T., & Taylor, N. M. I. (2023). Structural and mechanistic basis of substrate transport by the multidrug transporter MRP4. Structure, 31(11), 1407-1418.e6. https://doi.org/10.1016/j.str.2023.08.014

Vancouver

Bloch M, Raj I, Pape T, Taylor NMI. Structural and mechanistic basis of substrate transport by the multidrug transporter MRP4. Structure. 2023;31(11):1407-1418.e6. https://doi.org/10.1016/j.str.2023.08.014

Author

Bloch, Magnus ; Raj, Isha ; Pape, Tillmann ; Taylor, Nicholas M.I. / Structural and mechanistic basis of substrate transport by the multidrug transporter MRP4. In: Structure. 2023 ; Vol. 31, No. 11. pp. 1407-1418.e6.

Bibtex

@article{5e415c85e0b04d43ad409b9e95a0f7e3,
title = "Structural and mechanistic basis of substrate transport by the multidrug transporter MRP4",
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.",
keywords = "ABC transporter, ABCC4, cryo-EM, MRP4, multidrug resistance",
author = "Magnus Bloch and Isha Raj and Tillmann Pape and Taylor, {Nicholas M.I.}",
note = "Publisher Copyright: {\textcopyright} 2023 The Authors",
year = "2023",
doi = "10.1016/j.str.2023.08.014",
language = "English",
volume = "31",
pages = "1407--1418.e6",
journal = "Structure",
issn = "0969-2126",
publisher = "Cell Press",
number = "11",

}

RIS

TY - JOUR

T1 - Structural and mechanistic basis of substrate transport by the multidrug transporter MRP4

AU - Bloch, Magnus

AU - Raj, Isha

AU - Pape, Tillmann

AU - Taylor, Nicholas M.I.

N1 - Publisher Copyright: © 2023 The Authors

PY - 2023

Y1 - 2023

N2 - 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.

AB - 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.

KW - ABC transporter

KW - ABCC4

KW - cryo-EM

KW - MRP4

KW - multidrug resistance

U2 - 10.1016/j.str.2023.08.014

DO - 10.1016/j.str.2023.08.014

M3 - Journal article

C2 - 37683641

AN - SCOPUS:85175238653

VL - 31

SP - 1407-1418.e6

JO - Structure

JF - Structure

SN - 0969-2126

IS - 11

ER -

ID: 372967903