Inhibition and transport mechanisms of the ABC transporter hMRP5.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
06 Jun 2024
06 Jun 2024
Historique:
received:
12
09
2023
accepted:
24
05
2024
medline:
7
6
2024
pubmed:
7
6
2024
entrez:
6
6
2024
Statut:
epublish
Résumé
Human multidrug resistance protein 5 (hMRP5) effluxes anticancer and antivirus drugs, driving multidrug resistance. To uncover the mechanism of hMRP5, we determine six distinct cryo-EM structures, revealing an autoinhibitory N-terminal peptide that must dissociate to permit subsequent substrate recruitment. Guided by these molecular insights, we design an inhibitory peptide that could block substrate entry into the transport pathway. We also identify a regulatory motif, comprising a positively charged cluster and hydrophobic patches, within the first nucleotide-binding domain that modulates hMRP5 localization by engaging with membranes. By integrating our structural, biochemical, computational, and cell biological findings, we propose a model for hMRP5 conformational cycling and localization. Overall, this work provides mechanistic understanding of hMRP5 function, while informing future selective hMRP5 inhibitor development. More broadly, this study advances our understanding of the structural dynamics and inhibition of ABC transporters.
Identifiants
pubmed: 38844452
doi: 10.1038/s41467-024-49204-1
pii: 10.1038/s41467-024-49204-1
doi:
Substances chimiques
ATP-Binding Cassette Transporters
0
Multidrug Resistance-Associated Proteins
0
Peptides
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
4811Subventions
Organisme : National Natural Science Foundation of China (National Science Foundation of China)
ID : No. 32000850
Organisme : National Natural Science Foundation of China (National Science Foundation of China)
ID : No. 32371275
Organisme : National Natural Science Foundation of China (National Science Foundation of China)
ID : No. 32371300
Organisme : Guangdong Innovative and Entrepreneurial Research Team Program
ID : No. 2021ZT09Y104
Organisme : Natural Science Foundation of Zhejiang Province (Zhejiang Provincial Natural Science Foundation)
ID : No. LZ24C050003
Informations de copyright
© 2024. The Author(s).
Références
Wang, J. Q. et al. Multidrug resistance proteins (MRPs): structure, function and the overcoming of cancer multidrug resistance. Drug Resist. Updat. 54, 100743 (2021).
pubmed: 33513557
doi: 10.1016/j.drup.2021.100743
Kool, M. et al. Analysis of expression of cMOAT (MRP2), MRP3, MRP4 and MRP5, homologues of the multidrug resistance-associated protein gene (MRP1), in human cancer cell lines. Cancer Res. 57, 3537–3547 (1997).
pubmed: 9270026
Lu, J. F., Pokharel, D. & Bebawy, M. MRP1 and its role in anticancer drug resistance. Drug Metab. Rev. 47, 406–419 (2015).
pubmed: 26541366
doi: 10.3109/03602532.2015.1105253
Peters, K. W., Qi, J., Johnson, J. P., Watkins, S. C. & Frizzell, R. Role of snare proteins in CFTR and ENaC trafficking. Pflug. Arch. Eur. J. Phy. 443, 65–69 (2001).
doi: 10.1007/s004240100647
Chan, K. W., Zhang, H. & Logothetis, D. E. N-terminal transmembrane domain of the SUR controls trafficking and gating of Kir6 channel subunits. EMBO J. 22, 3833–3843 (2003).
pubmed: 12881418
pmcid: 169049
doi: 10.1093/emboj/cdg376
Scholl, D. et al. A topological switch in CFTR modulates channel activity and sensitivity to unfolding. Nat. Chem. Biol. 17, 989–997 (2021).
pubmed: 34341587
doi: 10.1038/s41589-021-00844-0
Minich, T. et al. The multidrug resistance protein 1 (MRP1), but not MRP5, mediates export of glutathione and glutathione disulfide from brain astrocytes. J. Neurochem. 97, 373–384 (2006).
pubmed: 16539673
doi: 10.1111/j.1471-4159.2006.03737.x
Johnson, Z. L. & Chen, J. Structural basis of substrate recognition by the multidrug resistance protein MRP1. Cell 168, 1075–1085.e9 (2017).
pubmed: 28238471
doi: 10.1016/j.cell.2017.01.041
Huang, Y. et al. Structural basis for substrate and inhibitor recognition of human multidrug transporter MRP4. Commun. Biol. 6, 549 (2023).
pubmed: 37217525
pmcid: 10202912
doi: 10.1038/s42003-023-04935-7
Meyer zu Schwabedissen, H. E. U. et al. Expression, localization, and function of MRP5 (ABCC5), a transporter for cyclic nucleotides, in human placenta and cultured human trophoblasts. Am. J. Pathol. 166, 39–48 (2005).
pubmed: 15631998
pmcid: 1602292
doi: 10.1016/S0002-9440(10)62230-4
de Wolf, C. J. F. et al. cGMP transport by vesicles from human and mouse erythrocytes. FEBS J. 274, 439–450 (2007).
pubmed: 17229149
doi: 10.1111/j.1742-4658.2006.05591.x
Dazert, P. et al. Expression and localization of the multidrug resistance protein 5 (MRP5/ABCC5), a cellular export pump for cyclic nucleotides, in human heart. Am. J. Pathol. 163, 1567–1577 (2003).
pubmed: 14507663
pmcid: 1868287
doi: 10.1016/S0002-9440(10)63513-4
Reid, G. et al. Characterization of the transport of nucleoside analog drugs by the human multidrug resistance proteins MRP4 and MRP5. Mol. Pharmacol. 63, 1094–1103 (2003).
pubmed: 12695538
doi: 10.1124/mol.63.5.1094
Wielinga, P. et al. The human multidrug resistance protein MRP5 transports folates and can mediate cellular resistance against antifolates. Cancer Res. 65, 4425–4430 (2005).
pubmed: 15899835
doi: 10.1158/0008-5472.CAN-04-2810
Hou, Y. et al. The FOXM1-ABCC5 axis contributes to paclitaxel resistance in nasopharyngeal carcinoma cells. Cell Death Dis. 8, e2659 (2017).
pubmed: 28277541
pmcid: 5386553
doi: 10.1038/cddis.2017.53
Lal, S. et al. Pharmacogenetics of ABCB5, ABCC5 and RLIP76 and doxorubicin pharmacokinetics in Asian breast cancer patients. Pharmacogenomics J. 17, 337–343 (2017).
pubmed: 26975227
doi: 10.1038/tpj.2016.17
Pratt, S. et al. The multidrug resistance protein 5 (ABCC5) confers resistance to 5-fluorouracil and transports its monophosphorylated metabolites. Mol. Cancer Ther. 4, 855–863 (2005).
pubmed: 15897250
doi: 10.1158/1535-7163.MCT-04-0291
Wijnholds, J. et al. Multidrug-resistance protein 5 is a multispecific organic anion transporter able to transport nucleotide analogs. Proc. Nat. Acad. Sci. USA 97, 7476–7481 (2000).
pubmed: 10840050
pmcid: 16570
doi: 10.1073/pnas.120159197
Oguri, T. et al. Increased expression of the MRP5 gene is associated with exposure to platinum drugs in lung cancer. Int. J. Cancer 86, 95–100 (2000).
pubmed: 10728601
doi: 10.1002/(SICI)1097-0215(20000401)86:1<95::AID-IJC15>3.0.CO;2-G
Guo, Y. et al. Expression of ABCC-type nucleotide exporters in blasts of adult acute myeloid leukemia: relation to long-term survival. Clin. l Cancer Res. 15, 1762–1769 (2009).
doi: 10.1158/1078-0432.CCR-08-0442
König, J. et al. Expression and localization of human multidrug resistance protein (ABCC) family members in pancreatic carcinoma. Int. J. Cancer 115, 359–367 (2005).
pubmed: 15688370
doi: 10.1002/ijc.20831
Alexiou, G. A. et al. Prognostic significance of MRP5 immunohistochemical expression in glioblastoma. Cancer Chemother. Pharmacol. 69, 1387–1391 (2012).
pubmed: 22278731
doi: 10.1007/s00280-012-1832-z
Hagmann, W., Jesnowski, R. & Löhr, J. M. Interdependence of gemcitabine treatment, transporter expression, and resistance in human pancreatic carcinoma cells. Neoplasia 12, 740–747 (2010).
pubmed: 20824050
pmcid: 2933694
doi: 10.1593/neo.10576
Maring, J. G., Groen, H. J. M., Wachters, F. M., Uges, D. R. A. & de Vries, E. G. E. Genetic factors influencing Pyrimidine-antagonist chemotherapy. Pharmacogenomics J. 5, 226–243 (2005).
pubmed: 16041392
doi: 10.1038/sj.tpj.6500320
Pratt, S., Chen, V., Perry, W. I., Starling, J. J. & Dantzig, A. H. Kinetic validation of the use of carboxydichlorofluorescein as a drug surrogate for MRP5-mediated transport. Eur. J. Pharm. Sci. 27, 524–532 (2006).
pubmed: 16337112
doi: 10.1016/j.ejps.2005.09.012
El-Readi, M. Z., Eid, S., Ashour, M. L., Tahrani, A. & Wink, M. Modulation of multidrug resistance in cancer cells by chelidonine and chelidonium majus alkaloids. Phytomedicine 20, 282–294 (2013).
pubmed: 23238299
doi: 10.1016/j.phymed.2012.11.005
Zheng, L. et al. Vandetanib (Zactima, ZD6474) antagonizes ABCC1- and ABCG2-mediated multidrug resistance by inhibition of their transport function. PLoS One 4, e5172 (2009).
pubmed: 19390592
pmcid: 2669214
doi: 10.1371/journal.pone.0005172
Wang, X. et al. Inhibition of tetramethylpyrazine on P-gp, MRP2, MRP3 and MRP5 in multidrug resistant human hepatocellular carcinoma cells. Oncol. Rep. 23, 861–867 (2009).
Wein, S. et al. Mediation of annexin 1 secretion by a probenecid-sensitive ABC-transporter in rat inflamed mucosa. Biochem. Pharmacol. 67, 1195–1202 (2004).
pubmed: 15006554
doi: 10.1016/j.bcp.2003.11.015
Jedlitschky, G., Burchell, B. & Keppler, D. The multidrug resistance protein 5 functions as an ATP-dependent export pump for cyclic nucleotides. J. Biol. Chem. 275, 30069–30074 (2000).
pubmed: 10893247
doi: 10.1074/jbc.M005463200
Boumendjel, A., Baubichon-Cortay, H., Trompier, D., Perrotton, T. & Di Pietro, A. Anticancer multidrug resistance mediated by MRP1: recent advances in the discovery of reversal agents. Med. Res. Rev. 25, 453–472 (2005).
pubmed: 15834856
doi: 10.1002/med.20032
Ogino, J., Moore, R. E., Patterson, G. M. L. & Smith, C. D. Dendroamides, new cyclic hexapeptides from a blue-green alga. Multidrug-resistance reversing activity of dendroamide A. J. Nat. Prod. 59, 581–586 (1996).
pubmed: 8786364
doi: 10.1021/np960178s
Xia, Z. & Smith, C. D. Total synthesis of dendroamide A, a novel cyclic peptide that reverses multiple drug resistance. J. Org. Chem. 66, 3459–3466 (2001).
pubmed: 11348130
doi: 10.1021/jo005783l
Pietz, H. L. et al. A macrocyclic peptide inhibitor traps MRP1 in a catalytically incompetent conformation. Proc. Nat. Acad. Sci. USA 120, 2017 (2023).
doi: 10.1073/pnas.2220012120
Oldham, M. L. et al. A mechanism of viral immune evasion revealed by cryo-EM analysis of the TAP transporter. Nature 529, 537–540 (2016).
pubmed: 26789246
pmcid: 4848044
doi: 10.1038/nature16506
Punjani, A., Rubinstein, J. L., Fleet, D. J. & Brubaker, M. A. cryoSPARC: algorithms for rapid unsupervised cryo-EM structure determination. Nat. Methods 14, 290–296 (2017).
pubmed: 28165473
doi: 10.1038/nmeth.4169
Kucukelbir, A., Sigworth, F. J. & Tagare, H. D. Quantifying the local resolution of cryo-EM density maps. Nat. Methods 11, 63–65 (2014).
pubmed: 24213166
doi: 10.1038/nmeth.2727
Lemmon, M. A. Membrane recognition by phospholipid-binding domains. Nat. Rev. Mol. Cell Biol. 9, 99–111 (2008).
pubmed: 18216767
doi: 10.1038/nrm2328
Di Paolo, G. & De Camilli, P. Phosphoinositides in cell regulation and membrane dynamics. Nature 443, 651–657 (2006).
pubmed: 17035995
doi: 10.1038/nature05185
Khandelwal, N. K. & Tomasiak, T. M. Structural basis for autoinhibition by the dephosphorylated regulatory domain of Ycf1. Nat. Commun. 15, 2389 (2024).
pubmed: 38493146
pmcid: 10944535
doi: 10.1038/s41467-024-46722-w
Huang, X. et al. Cryo-EM structure and molecular mechanism of abscisic acid transporter ABCG25. Nat. Plants 9, 1709–1719 (2023).
pubmed: 37666961
doi: 10.1038/s41477-023-01509-7
Lee, K. P. K., Chen, J. & MacKinnon, R. Molecular structure of human KATP in complex with ATP and ADP. Elife 6, 1–23 (2017).
doi: 10.7554/eLife.32481
Nosol, K. et al. Cryo-EM structures reveal distinct mechanisms of inhibition of the human multidrug transporter ABCB1. Proc. Nat. Acad. Sci. USA 117, 26245–26253 (2020).
pubmed: 33020312
pmcid: 7585025
doi: 10.1073/pnas.2010264117
Liu, F., Zhang, Z., Csanády, L., Gadsby, D. C. & Chen, J. Molecular structure of the human CFTR ion channel. Cell 169, 85–95.e8 (2017).
pubmed: 28340353
doi: 10.1016/j.cell.2017.02.024
Aller, S. G. et al. Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding. Science 323, 1718–1722 (2009).
pubmed: 19325113
pmcid: 2720052
doi: 10.1126/science.1168750
Taylor, N. M. I. et al. Structure of the human multidrug transporter ABCG2. Nature 546, 504–509 (2017).
pubmed: 28554189
doi: 10.1038/nature22345
Jackson, S. M. et al. Structural basis of small-molecule inhibition of human multidrug transporter ABCG2. Nat. Struct. Mol. Biol. 25, 333–340 (2018).
pubmed: 29610494
doi: 10.1038/s41594-018-0049-1
Ostedgaard, L. S., Baldursson, O., Vermeer, D. W., Welsh, M. J. & Robertson, A. D. A functional R domain from cystic fibrosis transmembrane conductance regulator is predominantly unstructured in solution. Proc. Nat. Acad. Sci. USA 97, 5657–5662 (2000).
pubmed: 10792060
pmcid: 25884
doi: 10.1073/pnas.100588797
Tan, N. C., Yu, P., Kwon, Y. U. & Kodadek, T. High-throughput evaluation of relative cell permeability between peptoids and peptides. Bioorg. Med. Chem. 16, 5853–5861 (2008).
pubmed: 18490170
pmcid: 2490712
doi: 10.1016/j.bmc.2008.04.074
Kwon, Y. U. & Kodadek, T. Quantitative comparison of the relative cell permeability of cyclic and linear peptides. Chem. Biol. 14, 671–677 (2007).
pubmed: 17584614
doi: 10.1016/j.chembiol.2007.05.006
Watson, J. L. et al. De novo design of protein structure and function with RFdiffusion. Nature 620, 1089–1100 (2023).
pubmed: 37433327
pmcid: 10468394
doi: 10.1038/s41586-023-06415-8
Wassenaar, T. A., Ingólfsson, H. I., Böckmann, R. A., Tieleman, D. P. & Marrink, S. J. Computational lipidomics with insane: a versatile tool for generating custom membranes for molecular simulations. J. Chem. Theory Comput. 11, 2144–2155 (2015).
pubmed: 26574417
doi: 10.1021/acs.jctc.5b00209
Souza, P. C. T. et al. Martini 3: a general purpose force field for coarse-grained molecular dynamics. Nat. Methods 18, 382–388 (2021).
pubmed: 33782607
doi: 10.1038/s41592-021-01098-3
Hsu, P. et al. CHARMM-GUI Martini Maker for modeling and simulation of complex bacterial membranes with lipopolysaccharides. J. Comput. Chem. 38, 2354–2363 (2017).
pubmed: 28776689
pmcid: 5939954
doi: 10.1002/jcc.24895
Abraham, M. J. et al. GROMACS: high performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX 1–2, 19–25 (2015).
doi: 10.1016/j.softx.2015.06.001
Colón-Ramos, D. A., La Riviere, P., Shroff, H. & Oldenbourg, R. Promoting transparency and reproducibility in enhanced molecular simulations. Nat. Methods 16, 670–673 (2019).
doi: 10.1038/s41592-019-0506-8
Andon, N. L. et al. Proteomic characterization of wheat amyloplasts using identification of proteins by tandem mass spectrometry. Proteomics 2, 1156–1168 (2002).
pubmed: 12362334
doi: 10.1002/1615-9861(200209)2:9<1156::AID-PROT1156>3.0.CO;2-4
Zheng, S. Q. et al. MotionCor2: anisotropic correction of beam-induced motion for improved cryo-electron microscopy. Nat. Methods 14, 331–332 (2017).
pubmed: 28250466
pmcid: 5494038
doi: 10.1038/nmeth.4193
Scheres, S. H. W. & Chen, S. Prevention of overfitting in cryo-EM structure determination. Nat. Methods 9, 853–854 (2012).
pubmed: 22842542
pmcid: 4912033
doi: 10.1038/nmeth.2115
Kelley, L. A., Mezulis, S., Yates, C. M., Wass, M. N. & Sternberg, M. J. E. The Phyre2 web portal for protein modeling, prediction and analysis. Nat. Protoc. 10, 845–858 (2015).
pubmed: 25950237
pmcid: 5298202
doi: 10.1038/nprot.2015.053
Pettersen, E. F. et al. UCSF Chimera-a visualization system for exploratory research and analysis. J. Comput. Chem. 25, 1605–1612 (2004).
pubmed: 15264254
doi: 10.1002/jcc.20084
Emsley, P. & Cowtan, K. Coot: model-building tools for molecular graphics. Acta Crystallogr. D. Biol. Crystallogr. 60, 2126–2132 (2004).
pubmed: 15572765
doi: 10.1107/S0907444904019158
Adams, P. D. et al. PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr. D. Biol. Crystallogr. 66, 213–221 (2010).
pubmed: 20124702
pmcid: 2815670
doi: 10.1107/S0907444909052925