8kci

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ATP-bound hMRP5 outward-open

Structural highlights

8kci is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:Electron Microscopy, Resolution 3.94Å
Ligands:ATP, MG
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

MRP5_HUMAN ATP-dependent transporter of the ATP-binding cassette (ABC) family that actively extrudes physiological compounds, and xenobiotics from cells. Mediates ATP-dependent transport of endogenous metabolites such as cAMP and cGMP, folic acid and N-lactoyl-amino acids (in vitro) (PubMed:10893247, PubMed:12637526, PubMed:12695538, PubMed:15899835, PubMed:17229149, PubMed:25964343). Acts also as a general glutamate conjugate and analog transporter that can limit the brain levels of endogenous metabolites, drugs, and toxins (PubMed:26515061). Confers resistance to the antiviral agent PMEA (PubMed:12695538). Able to transport several anticancer drugs including methotrexate, and nucleotide analogs in vitro, however it does with low affinity, thus the exact role of ABCC5 in mediating resistance still needs to be elucidated (PubMed:10840050, PubMed:12435799, PubMed:12695538, PubMed:15899835). Acts as a heme transporter required for the translocation of cytosolic heme to the secretory pathway (PubMed:24836561). May play a role in energy metabolism by regulating the glucagon-like peptide 1 (GLP-1) secretion from enteroendocrine cells (By similarity).[UniProtKB:Q9R1X5][1] [2] [3] [4] [5] [6] [7] [8] [9] [10]

Publication Abstract from PubMed

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.

Inhibition and transport mechanisms of the ABC transporter hMRP5.,Huang Y, Xue C, Bu R, Wu C, Li J, Zhang J, Chen J, Shi Z, Chen Y, Wang Y, Liu Z Nat Commun. 2024 Jun 6;15(1):4811. doi: 10.1038/s41467-024-49204-1. PMID:38844452[11]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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References

  1. ↑ Wijnholds J, Mol CA, van Deemter L, de Haas M, Scheffer GL, Baas F, Beijnen JH, Scheper RJ, Hatse S, De Clercq E, Balzarini J, Borst P. Multidrug-resistance protein 5 is a multispecific organic anion transporter able to transport nucleotide analogs. Proc Natl Acad Sci U S A. 2000 Jun 20;97(13):7476-81. PMID:10840050 doi:10.1073/pnas.120159197
  2. ↑ Jedlitschky G, Burchell B, Keppler D. The multidrug resistance protein 5 functions as an ATP-dependent export pump for cyclic nucleotides. J Biol Chem. 2000 Sep 29;275(39):30069-74. PMID:10893247 doi:10.1074/jbc.M005463200
  3. ↑ Wielinga PR, Reid G, Challa EE, van der Heijden I, van Deemter L, de Haas M, Mol C, Kuil AJ, Groeneveld E, Schuetz JD, Brouwer C, De Abreu RA, Wijnholds J, Beijnen JH, Borst P. Thiopurine metabolism and identification of the thiopurine metabolites transported by MRP4 and MRP5 overexpressed in human embryonic kidney cells. Mol Pharmacol. 2002 Dec;62(6):1321-31. PMID:12435799 doi:10.1124/mol.62.6.1321
  4. ↑ Wielinga PR, van der Heijden I, Reid G, Beijnen JH, Wijnholds J, Borst P. Characterization of the MRP4 from intact cells. J Biol Chem. 2003 May 16;278(20):17664-71. PMID:12637526 doi:10.1074/jbc.M212723200
  5. ↑ Reid G, Wielinga P, Zelcer N, De Haas M, Van Deemter L, Wijnholds J, Balzarini J, Borst P. Characterization of the transport of nucleoside analog drugs by the human multidrug resistance proteins MRP4 and MRP5. Mol Pharmacol. 2003 May;63(5):1094-103. PMID:12695538 doi:10.1124/mol.63.5.1094
  6. ↑ Wielinga P, Hooijberg JH, Gunnarsdottir S, Kathmann I, Reid G, Zelcer N, van der Born K, de Haas M, van der Heijden I, Kaspers G, Wijnholds J, Jansen G, Peters G, Borst P. The human multidrug resistance protein MRP5 transports folates and can mediate cellular resistance against antifolates. Cancer Res. 2005 May 15;65(10):4425-30. PMID:15899835 doi:10.1158/0008-5472.CAN-04-2810
  7. ↑ de Wolf CJ, Yamaguchi H, van der Heijden I, Wielinga PR, Hundscheid SL, Ono N, Scheffer GL, de Haas M, Schuetz JD, Wijnholds J, Borst P. cGMP transport by vesicles from human and mouse erythrocytes. FEBS J. 2007 Jan;274(2):439-50. PMID:17229149 doi:10.1111/j.1742-4658.2006.05591.x
  8. ↑ Korolnek T, Zhang J, Beardsley S, Scheffer GL, Hamza I. Control of metazoan heme homeostasis by a conserved multidrug resistance protein. Cell Metab. 2014 Jun 3;19(6):1008-19. PMID:24836561 doi:10.1016/j.cmet.2014.03.030
  9. ↑ Jansen RS, Addie R, Merkx R, Fish A, Mahakena S, Bleijerveld OB, Altelaar M, IJlst L, Wanders RJ, Borst P, van de Wetering K. N-lactoyl-amino acids are ubiquitous metabolites that originate from CNDP2-mediated reverse proteolysis of lactate and amino acids. Proc Natl Acad Sci U S A. 2015 May 26;112(21):6601-6. doi:, 10.1073/pnas.1424638112. Epub 2015 May 11. PMID:25964343 doi:http://dx.doi.org/10.1073/pnas.1424638112
  10. ↑ Jansen RS, Mahakena S, de Haas M, Borst P, van de Wetering K. ATP-binding Cassette Subfamily C Member 5 (ABCC5) Functions as an Efflux Transporter of Glutamate Conjugates and Analogs. J Biol Chem. 2015 Dec 18;290(51):30429-40. PMID:26515061 doi:10.1074/jbc.M115.692103
  11. ↑ Huang Y, Xue C, Bu R, Wu C, Li J, Zhang J, Chen J, Shi Z, Chen Y, Wang Y, Liu Z. Inhibition and transport mechanisms of the ABC transporter hMRP5. Nat Commun. 2024 Jun 6;15(1):4811. PMID:38844452 doi:10.1038/s41467-024-49204-1

Contents


PDB ID 8kci

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