8rq3
From Proteopedia
(Difference between revisions)
(New page: '''Unreleased structure''' The entry 8rq3 is ON HOLD Authors: Description: Category: Unreleased Structures) |
|||
| (2 intermediate revisions not shown.) | |||
| Line 1: | Line 1: | ||
| - | '''Unreleased structure''' | ||
| - | + | ==Cryo-em structure of the rat Multidrug resistance-associated protein 2 (rMrp2) in an autoinhibited state (nucleotide-free)== | |
| + | <StructureSection load='8rq3' size='340' side='right'caption='[[8rq3]], [[Resolution|resolution]] 3.21Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[8rq3]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8RQ3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8RQ3 FirstGlance]. <br> | ||
| + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.21Å</td></tr> | ||
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8rq3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8rq3 OCA], [https://pdbe.org/8rq3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8rq3 RCSB], [https://www.ebi.ac.uk/pdbsum/8rq3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8rq3 ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Disease == | ||
| + | [https://www.uniprot.org/uniprot/MRP2_RAT MRP2_RAT] Defects in Abcc2 are a cause of hereditary conjugated hyperbilirubinemia (EHBR).<ref>PMID:8599091</ref> [REFERENCE:3] | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/MRP2_RAT MRP2_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]<ref>PMID:10220572</ref> <ref>PMID:10421658</ref> <ref>PMID:11248200</ref> <ref>PMID:8662992</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Multidrug 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<ref>PMID:38438394</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 8rq3" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Rattus norvegicus]] | ||
| + | [[Category: Beis K]] | ||
| + | [[Category: Mazza T]] | ||
Current revision
Cryo-em structure of the rat Multidrug resistance-associated protein 2 (rMrp2) in an autoinhibited state (nucleotide-free)
| |||||||||||
