| Structural highlights
Function
MRP4_HUMAN ATP-dependent transporter of the ATP-binding cassette (ABC) family that actively extrudes physiological compounds and xenobiotics from cells. Transports a range of endogenous molecules that have a key role in cellular communication and signaling, including cyclic nucleotides such as cyclic AMP (cAMP) and cyclic GMP (cGMP), bile acids, steroid conjugates, urate, and prostaglandins (PubMed:11856762, PubMed:12523936, PubMed:12835412, PubMed:12883481, PubMed:15364914, PubMed:15454390, PubMed:16282361, PubMed:17959747, PubMed:18300232, PubMed:26721430). Mediates the ATP-dependent efflux of glutathione conjugates such as leukotriene C4 (LTC4) and leukotriene B4 (LTB4) too. The presence of GSH is necessary for the ATP-dependent transport of LTB4, whereas GSH is not required for the transport of LTC4 (PubMed:17959747). Mediates the cotransport of bile acids with reduced glutathione (GSH) (PubMed:12523936, PubMed:12883481, PubMed:16282361). Transports a wide range of drugs and their metabolites, including anticancer, antiviral and antibiotics molecules (PubMed:11856762, PubMed:12105214, PubMed:15454390, PubMed:17344354, PubMed:18300232). Confers resistance to anticancer agents such as methotrexate (PubMed:11106685).[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13]
Publication Abstract from PubMed
Human multidrug resistance protein 4 (hMRP4, also known as ABCC4), with a representative topology of the MRP subfamily, translocates various substrates across the membrane and contributes to the development of multidrug resistance. However, the underlying transport mechanism of hMRP4 remains unclear due to a lack of high-resolution structures. Here, we use cryogenic electron microscopy (cryo-EM) to resolve its near-atomic structures in the apo inward-open and the ATP-bound outward-open states. We also capture the PGE1 substrate-bound structure and, importantly, the inhibitor-bound structure of hMRP4 in complex with sulindac, revealing that substrate and inhibitor compete for the same hydrophobic binding pocket although with different binding modes. Moreover, our cryo-EM structures, together with molecular dynamics simulations and biochemical assay, shed light on the structural basis of the substrate transport and inhibition mechanism, with implications for the development of hMRP4-targeted drugs.
Structural basis for substrate and inhibitor recognition of human multidrug transporter MRP4.,Huang Y, Xue C, Wang L, Bu R, Mu J, Wang Y, Liu Z Commun Biol. 2023 May 22;6(1):549. doi: 10.1038/s42003-023-04935-7. PMID:37217525[14]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Lee K, Klein-Szanto AJ, Kruh GD. Analysis of the MRP4 drug resistance profile in transfected NIH3T3 cells. J Natl Cancer Inst. 2000 Dec 6;92(23):1934-40. PMID:11106685 doi:10.1093/jnci/92.23.1934
- ↑ van Aubel RAMH, Smeets PHE, Peters JGP, Bindels RJM, Russel FGM. The MRP4/ABCC4 gene encodes a novel apical organic anion transporter in human kidney proximal tubules: putative efflux pump for urinary cAMP and cGMP. J Am Soc Nephrol. 2002 Mar;13(3):595-603. PMID:11856762 doi:10.1681/ASN.V133595
- ↑ Adachi M, Sampath J, Lan LB, Sun D, Hargrove P, Flatley R, Tatum A, Edwards MZ, Wezeman M, Matherly L, Drake R, Schuetz J. Expression of MRP4 confers resistance to ganciclovir and compromises bystander cell killing. J Biol Chem. 2002 Oct 11;277(41):38998-9004. PMID:12105214 doi:10.1074/jbc.M203262200
- ↑ Zelcer N, Reid G, Wielinga P, Kuil A, van der Heijden I, Schuetz JD, Borst P. Steroid and bile acid conjugates are substrates of human multidrug-resistance protein (MRP) 4 (ATP-binding cassette C4). Biochem J. 2003 Apr 15;371(Pt 2):361-7. PMID:12523936 doi:10.1042/BJ20021886
- ↑ Reid G, Wielinga P, Zelcer N, van der Heijden I, Kuil A, de Haas M, Wijnholds J, Borst P. The human multidrug resistance protein MRP4 functions as a prostaglandin efflux transporter and is inhibited by nonsteroidal antiinflammatory drugs. Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9244-9. PMID:12835412 doi:10.1073/pnas.1033060100
- ↑ Rius M, Nies AT, Hummel-Eisenbeiss J, Jedlitschky G, Keppler D. Cotransport of reduced glutathione with bile salts by MRP4 (ABCC4) localized to the basolateral hepatocyte membrane. Hepatology. 2003 Aug;38(2):374-84. PMID:12883481 doi:10.1053/jhep.2003.50331
- ↑ Sauna ZE, Nandigama K, Ambudkar SV. Multidrug resistance protein 4 (ABCC4)-mediated ATP hydrolysis: effect of transport substrates and characterization of the post-hydrolysis transition state. J Biol Chem. 2004 Nov 19;279(47):48855-64. PMID:15364914 doi:10.1074/jbc.M408849200
- ↑ Van Aubel RA, Smeets PH, van den Heuvel JJ, Russel FG. Human organic anion transporter MRP4 (ABCC4) is an efflux pump for the purine end metabolite urate with multiple allosteric substrate binding sites. Am J Physiol Renal Physiol. 2005 Feb;288(2):F327-33. PMID:15454390 doi:10.1152/ajprenal.00133.2004
- ↑ Rius M, Hummel-Eisenbeiss J, Hofmann AF, Keppler D. Substrate specificity of human ABCC4 (MRP4)-mediated cotransport of bile acids and reduced glutathione. Am J Physiol Gastrointest Liver Physiol. 2006 Apr;290(4):G640-9. PMID:16282361 doi:10.1152/ajpgi.00354.2005
- ↑ Ci L, Kusuhara H, Adachi M, Schuetz JD, Takeuchi K, Sugiyama Y. Involvement of MRP4 (ABCC4) in the luminal efflux of ceftizoxime and cefazolin in the kidney. Mol Pharmacol. 2007 Jun;71(6):1591-7. PMID:17344354 doi:10.1124/mol.106.031823
- ↑ Rius M, Hummel-Eisenbeiss J, Keppler D. ATP-dependent transport of leukotrienes B4 and C4 by the multidrug resistance protein ABCC4 (MRP4). J Pharmacol Exp Ther. 2008 Jan;324(1):86-94. PMID:17959747 doi:10.1124/jpet.107.131342
- ↑ Janke D, Mehralivand S, Strand D, Gödtel-Armbrust U, Habermeier A, Gradhand U, Fischer C, Toliat MR, Fritz P, Zanger UM, Schwab M, Fromm MF, Nürnberg P, Wojnowski L, Closs EI, Lang T. 6-mercaptopurine and 9-(2-phosphonyl-methoxyethyl) adenine (PMEA) transport altered by two missense mutations in the drug transporter gene ABCC4. Hum Mutat. 2008 May;29(5):659-69. PMID:18300232 doi:10.1002/humu.20694
- ↑ Miah MF, Conseil G, Cole SP. N-linked glycans do not affect plasma membrane localization of multidrug resistance protein 4 (MRP4) but selectively alter its prostaglandin E2 transport activity. Biochem Biophys Res Commun. 2016 Jan 22;469(4):954-9. PMID:26721430 doi:10.1016/j.bbrc.2015.12.095
- ↑ Huang Y, Xue C, Wang L, Bu R, Mu J, Wang Y, Liu Z. Structural basis for substrate and inhibitor recognition of human multidrug transporter MRP4. Commun Biol. 2023 May 22;6(1):549. PMID:37217525 doi:10.1038/s42003-023-04935-7
|
