ATP Binding Enables Substrate Release from Multidrug Resistance Protein 1
- PMID: 29290467
- DOI: 10.1016/j.cell.2017.12.005
ATP Binding Enables Substrate Release from Multidrug Resistance Protein 1
Abstract
The multidrug resistance protein MRP1 is an ATP-driven pump that confers resistance to chemotherapy. Previously, we have shown that intracellular substrates are recruited to a bipartite binding site when the transporter rests in an inward-facing conformation. A key question remains: how are high-affinity substrates transferred across the membrane and released outside the cell? Using electron cryomicroscopy, we show here that ATP binding opens the transport pathway to the extracellular space and reconfigures the substrate-binding site such that it relinquishes its affinity for substrate. Thus, substrate is released prior to ATP hydrolysis. With this result, we now have a complete description of the conformational cycle that enables substrate transfer in a eukaryotic ABC exporter.
Keywords: ABC transporter; ABCC1; MRP1; cryo-EM; multidrug resistance; outward facing.
Copyright © 2017 Elsevier Inc. All rights reserved.
Similar articles
-
Structural Basis of Substrate Recognition by the Multidrug Resistance Protein MRP1.Cell. 2017 Mar 9;168(6):1075-1085.e9. doi: 10.1016/j.cell.2017.01.041. Epub 2017 Feb 23. Cell. 2017. PMID: 28238471
-
In vivo FRET analyses reveal a role of ATP hydrolysis-associated conformational changes in human P-glycoprotein.J Biol Chem. 2020 Apr 10;295(15):5002-5011. doi: 10.1074/jbc.RA119.012042. Epub 2020 Feb 28. J Biol Chem. 2020. PMID: 32111736 Free PMC article.
-
A macrocyclic peptide inhibitor traps MRP1 in a catalytically incompetent conformation.Proc Natl Acad Sci U S A. 2023 Mar 14;120(11):e2220012120. doi: 10.1073/pnas.2220012120. Epub 2023 Mar 9. Proc Natl Acad Sci U S A. 2023. PMID: 36893260 Free PMC article.
-
Multidrug resistance protein 1 (MRP1, ABCC1), a "multitasking" ATP-binding cassette (ABC) transporter.J Biol Chem. 2014 Nov 7;289(45):30880-8. doi: 10.1074/jbc.R114.609248. Epub 2014 Oct 3. J Biol Chem. 2014. PMID: 25281745 Free PMC article. Review.
-
ATP-binding Cassette Exporters: Structure and Mechanism with a Focus on P-glycoprotein and MRP1.Curr Med Chem. 2019;26(7):1062-1078. doi: 10.2174/0929867324666171012105143. Curr Med Chem. 2019. PMID: 29022498 Review.
Cited by
-
The impact of ATP-binding cassette transporters on metabolic diseases.Nutr Metab (Lond). 2020 Aug 3;17:61. doi: 10.1186/s12986-020-00478-4. eCollection 2020. Nutr Metab (Lond). 2020. PMID: 32774439 Free PMC article. Review.
-
Cytotoxicity and reversal effect of sertraline, fluoxetine, and citalopram on MRP1- and MRP7-mediated MDR.Front Pharmacol. 2023 Nov 2;14:1290255. doi: 10.3389/fphar.2023.1290255. eCollection 2023. Front Pharmacol. 2023. PMID: 38026953 Free PMC article.
-
Multidrug Resistance in Mammals and Fungi-From MDR to PDR: A Rocky Road from Atomic Structures to Transport Mechanisms.Int J Mol Sci. 2021 Apr 30;22(9):4806. doi: 10.3390/ijms22094806. Int J Mol Sci. 2021. PMID: 33946618 Free PMC article. Review.
-
Insights on the structure-function relationship of human multidrug resistance protein 7 (MRP7/ABCC10) from molecular dynamics simulations and docking studies.MedComm (2020). 2021 Mar 25;2(2):221-235. doi: 10.1002/mco2.65. eCollection 2021 Jun. MedComm (2020). 2021. PMID: 34766143 Free PMC article.
-
Conserved amino acids in the region connecting membrane spanning domain 1 to nucleotide binding domain 1 are essential for expression of the MRP1 (ABCC1) transporter.PLoS One. 2021 Feb 11;16(2):e0246727. doi: 10.1371/journal.pone.0246727. eCollection 2021. PLoS One. 2021. PMID: 33571281 Free PMC article.
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Research Materials
