| Structural highlights
Function
S47A1_HUMAN Multidrug efflux pump that functions as a H(+)/organic cation antiporter (PubMed:16330770, PubMed:17509534). Plays a physiological role in the excretion of cationic compounds including endogenous metabolites, drugs, toxins through the kidney and liver, into urine and bile respectively (PubMed:16330770, PubMed:17495125, PubMed:17509534, PubMed:17582384, PubMed:18305230, PubMed:19158817, PubMed:21128598, PubMed:24961373). Mediates the efflux of endogenous compounds such as creatinine, vitamin B1/thiamine, agmatine and estrone-3-sulfate (PubMed:16330770, PubMed:17495125, PubMed:17509534, PubMed:17582384, PubMed:18305230, PubMed:19158817, PubMed:21128598, PubMed:24961373). May also contribute to regulate the transport of cationic compounds in testis across the blood-testis-barrier (Probable).[1] [2] [3] [4] [5] [6] [7] [8] [9]
Publication Abstract from PubMed
Human MATE1 (multidrug and toxin extrusion protein 1) is highly expressed in the kidney and liver, where it mediates the final step in the excretion of a broad range of cationic drugs, including the antidiabetic drug metformin, into the urine and bile. This transport process is essential for drug clearance and also affects therapeutic efficacy. To understand the molecular basis of drug recognition by hMATE1, we determined cryo-electron microscopy structures of the transporter in complex with the substrates 1-methyl-4-phenylpyridinium (MPP) and metformin and with the inhibitor cimetidine. The structures reveal a shared binding site located in a negatively charged pocket in the C-lobe of the protein. We functionally validated key interactions using radioactivity-based cellular uptake assays using hMATE1 mutants. Molecular dynamics simulations provide insights into the different binding modes and dynamic behaviour of the ligands within the pocket. Collectively, these findings define the structural basis of hMATE1 substrate specificity and shed light on its role in drug transport and drug-drug interactions.
Structural basis of drug recognition by human MATE1 transporter.,Romane K, Peteani G, Mukherjee S, Kowal J, Rossi L, Hou J, Kossiakoff AA, Lemmin T, Locher KP Nat Commun. 2025 Oct 27;16(1):9444. doi: 10.1038/s41467-025-64490-z. PMID:41145429[10]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Otsuka M, Matsumoto T, Morimoto R, Arioka S, Omote H, Moriyama Y. A human transporter protein that mediates the final excretion step for toxic organic cations. Proc Natl Acad Sci U S A. 2005 Dec 13;102(50):17923-8. PMID:16330770 doi:10.1073/pnas.0506483102
- ↑ Chen Y, Zhang S, Sorani M, Giacomini KM. Transport of paraquat by human organic cation transporters and multidrug and toxic compound extrusion family. J Pharmacol Exp Ther. 2007 Aug;322(2):695-700. PMID:17495125 doi:10.1124/jpet.107.123554
- ↑ Tanihara Y, Masuda S, Sato T, Katsura T, Ogawa O, Inui K. Substrate specificity of MATE1 and MATE2-K, human multidrug and toxin extrusions/H(+)-organic cation antiporters. Biochem Pharmacol. 2007 Jul 15;74(2):359-71. PMID:17509534 doi:10.1016/j.bcp.2007.04.010
- ↑ Yokoo S, Yonezawa A, Masuda S, Fukatsu A, Katsura T, Inui K. Differential contribution of organic cation transporters, OCT2 and MATE1, in platinum agent-induced nephrotoxicity. Biochem Pharmacol. 2007 Aug 1;74(3):477-87. PMID:17582384 doi:10.1016/j.bcp.2007.03.004
- ↑ Matsumoto T, Kanamoto T, Otsuka M, Omote H, Moriyama Y. Role of glutamate residues in substrate recognition by human MATE1 polyspecific H+/organic cation exporter. Am J Physiol Cell Physiol. 2008 Apr;294(4):C1074-8. PMID:18305230 doi:10.1152/ajpcell.00504.2007
- ↑ Kajiwara M, Terada T, Ogasawara K, Iwano J, Katsura T, Fukatsu A, Doi T, Inui K. Identification of multidrug and toxin extrusion (MATE1 and MATE2-K) variants with complete loss of transport activity. J Hum Genet. 2009 Jan;54(1):40-6. PMID:19158817 doi:10.1038/jhg.2008.1
- ↑ Winter TN, Elmquist WF, Fairbanks CA. OCT2 and MATE1 provide bidirectional agmatine transport. Mol Pharm. 2011 Feb 7;8(1):133-42. PMID:21128598 doi:10.1021/mp100180a
- ↑ Chen L, Shu Y, Liang X, Chen EC, Yee SW, Zur AA, Li S, Xu L, Keshari KR, Lin MJ, Chien HC, Zhang Y, Morrissey KM, Liu J, Ostrem J, Younger NS, Kurhanewicz J, Shokat KM, Ashrafi K, Giacomini KM. OCT1 is a high-capacity thiamine transporter that regulates hepatic steatosis and is a target of metformin. Proc Natl Acad Sci U S A. 2014 Jul 8;111(27):9983-8. PMID:24961373 doi:10.1073/pnas.1314939111
- ↑ Hau RK, Klein RR, Wright SH, Cherrington NJ. Localization of Xenobiotic Transporters Expressed at the Human Blood-Testis Barrier. Drug Metab Dispos. 2022 Jun;50(6):770-780. PMID:35307651 doi:10.1124/dmd.121.000748
- ↑ Romane K, Peteani G, Mukherjee S, Kowal J, Rossi L, Hou J, Kossiakoff AA, Lemmin T, Locher KP. Structural basis of drug recognition by human MATE1 transporter. Nat Commun. 2025 Oct 27;16(1):9444. PMID:41145429 doi:10.1038/s41467-025-64490-z
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