3.A.1.208.8
Drug resistance pump; ABCC1 (MRP1), exports chemotherapeutic agents, organic anions such as leukotriene C₄ (LTC₄), 17-β-estradiol 17-β-D-glucuronide, glucuronide-X (E₂17βG, etoposide-glucuronide), estrone-3-sulfate, folic acid and methotrexate, arsenic triglutathione, arsenic and antimonial oxyanions, glutathione (GSH), GSSG, glutathione conjugates (GSH-X; LTC₄, DNP-SG, EA-SG, NEH-SG), sulfate-X (E₁S, DHEAS), HIV protease inhibitors, anthracyclines, epipodophyllotoxins, and Vinca alkaloids. Changing charged residues in TMS6 (K332, H335 and D336) gave rise to specific changes in specificity (Chen et al., 2006; Haimeur et al., 2002; Leslie et al., 2004).  Also, mutations in TMS 10 alter substrate binding and export of drugs (Zhang et al. 2006). MDR1 also exports cobalamine (Vitamin B₁₂) (Beedholm-Ebsen et al., 2010) and cytotoxic metals including antimony, mercuric ions, arsenate and arsenite, but not copper, chromium, cobalt and aluminum, often as glutathione conjugates (Aleo et al., 2005; Vernhet et al., 2000). Notch1 regulates the expression in cultured cancer cells (Cho et al., 2011).  Structural and functional properties of MRP1 have been reviewed comprehensively (He et al. 2011).  Fluorescent substrates have been identified (Strouse et al. 2013).  It pumps out sulfur mustards and nitrogen mustards (mechlorethamine, HN2), potent vesicants developed as chemical warfare agents (Udasin et al. 2015). It has 3 membrane domains with a total of 17 TMSs. Loss of the aromatic side chain at position 583 impairs the release of ADP and thus effectively locks the transporter in a low-affinity solute binding state (Weigl et al. 2018). MRP1 Tyr₁₁₈₉ and Tyr₁₁₉₀, unlike the corresponding residues in SUR1, are not involved in its differential sensitivity to sulfonylureas, but nevertheless, may be involved in the transport activity of MRP1, especially with respect to glutathione, GSH (Conseil et al. 2005). Modulators of MRP1 activity have been found (Möhle et al. 2020). Glu₁₂₀₄ serves a dual role in membrane expression of MRP1 and in a step in its catalytic cycle subsequent to initial substrate binding (Situ et al. 2004). The cotransport mechanism of GSH with anticancer drugs by MRP1 has been examined (Zhao et al. 2020). The first cytoplasmic loop in the core structure of ABCC1 contains multiple amino acids essential for Its expression (Conseil and Cole 2021). Carboplatin, paclitaxel and topotecan bind specifically to Asn510 in transmembrane domain 1 of MRP1 (Haque et al. 2022). The farnesyl protein transferase inhibitor, lonafarnib (SCH66336), is an inhibitor of multidrug resistance proteins 1 and 2, Mrp1 and Mrp2 (Wang and Johnson 2003). A macrocyclic peptide, named CPI1, inhibits MRP1 with nanomolar potency but shows minimal inhibition of P-glycoprotein. A cryo-EM structure at 3.27 Å resolution shows that CPI1 binds MRP1 at the same location as the physiological substrate leukotriene C4 (LTC₄). Residues that interact with both ligands contain large, flexible side chains that can form a variety of interactions, revealing how MRP1 recognizes multiple structurally unrelated molecules. CPI1 binding prevents the conformational changes necessary for ATP hydrolysis and substrate transport (Pietz et al. 2023). ABCB1 and ABCC1 function during the TGF-β-induced epithelial-mesenchymal transition, and the relationship between multidrug resistance and tumor progression has been considered (da Costa et al. 2023).