8rq3
Cryo-em structure of the rat Multidrug resistance-associated protein 2 (rMrp2) in an autoinhibited state (nucleotide-free)
Structural highlights
DiseaseMRP2_RAT Defects in Abcc2 are a cause of hereditary conjugated hyperbilirubinemia (EHBR).[1] [REFERENCE:3] FunctionMRP2_RAT ATP-dependent transporter of the ATP-binding cassette (ABC) family that binds and hydrolyzes ATP to enable active transport of various substrates including many drugs, toxicants and endogenous compound across cell membranes. Transports a wide variety of conjugated organic anions such as sulfate-, glucuronide- and glutathione (GSH)-conjugates of endo- and xenobiotics substrates (PubMed:10220572, PubMed:10421658, PubMed:11248200, PubMed:8662992). Mediates hepatobiliary excretion of mono- and bis-glucuronidated bilirubin molecules and therefore play an important role in bilirubin detoxification (PubMed:10421658). Mediates also hepatobiliary excretion of others glucuronide conjugates such as 17beta-estradiol 17-glucosiduronic acid and leukotriene C4 (PubMed:10220572, PubMed:8662992). Transports sulfated bile salt such as taurolithocholate sulfate (PubMed:11248200). Transports various anticancer drugs, such as anthracycline, vinca alkaloid and methotrexate and HIV-drugs such as protease inhibitors (By similarity).[UniProtKB:Q92887][2] [3] [4] [5] Publication Abstract from PubMedMultidrug resistance-associated protein 2 (MRP2/ABCC2) is a polyspecific efflux transporter of organic anions expressed in hepatocyte canalicular membranes. MRP2 dysfunction, in Dubin-Johnson syndrome or by off-target inhibition, for example by the uricosuric drug probenecid, elevates circulating bilirubin glucuronide and is a cause of jaundice. Here, we determine the cryo-EM structure of rat Mrp2 (rMrp2) in an autoinhibited state and in complex with probenecid. The autoinhibited state exhibits an unusual conformation for this class of transporter in which the regulatory domain is folded within the transmembrane domain cavity. In vitro phosphorylation, mass spectrometry and transport assays show that phosphorylation of the regulatory domain relieves this autoinhibition and enhances rMrp2 transport activity. The in vitro data is confirmed in human hepatocyte-like cells, in which inhibition of endogenous kinases also reduces human MRP2 transport activity. The drug-bound state reveals two probenecid binding sites that suggest a dynamic interplay with autoinhibition. Mapping of the Dubin-Johnson mutations onto the rodent structure indicates that many may interfere with the transition between conformational states. Structural basis for the modulation of MRP2 activity by phosphorylation and drugs.,Mazza T, Roumeliotis TI, Garitta E, Drew D, Rashid ST, Indiveri C, Choudhary JS, Linton KJ, Beis K Nat Commun. 2024 Mar 4;15(1):1983. doi: 10.1038/s41467-024-46392-8. PMID:38438394[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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