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TitleStructural basis for the modulation of MRP2 activity by phosphorylation and drugs.
Journal, issue, pagesNat Commun, Vol. 15, Issue 1, Page 1983, Year 2024
Publish dateMar 4, 2024
AuthorsTiziano Mazza / Theodoros I Roumeliotis / Elena Garitta / David Drew / S Tamir Rashid / Cesare Indiveri / Jyoti S Choudhary / Kenneth J Linton / Konstantinos Beis /
PubMed AbstractMultidrug resistance-associated protein 2 (MRP2/ABCC2) is a polyspecific efflux transporter of organic anions expressed in hepatocyte canalicular membranes. MRP2 dysfunction, in Dubin-Johnson ...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.
External linksNat Commun / PubMed:38438394 / PubMed Central
MethodsEM (single particle)
Resolution3.21 - 3.45 Å
Structure data

19431

8rq3

EMDB-19431, PDB-8rq3:
Cryo-em structure of the rat Multidrug resistance-associated protein 2 (rMrp2) in an autoinhibited state (nucleotide-free)
Method: EM (single particle) / Resolution: 3.21 Å

19433

8rq4

EMDB-19433, PDB-8rq4:
Cryo-em structure of the rat Multidrug resistance-associated protein 2 (rMrp2) in complex with probenecid
Method: EM (single particle) / Resolution: 3.45 Å

Chemicals

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

ChemComp-RTO:
4-(dipropylsulfamoyl)benzoic acid

Source
  • rattus norvegicus (Norway rat)
KeywordsTRANSPORT PROTEIN / Multidrug resistance-associated protein 2 (rMrp2) in an autoinhibited state (nucleotide-free)

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