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TitleStructural Basis of Substrate Recognition by the Multidrug Resistance Protein MRP1.
Journal, issue, pagesCell, Vol. 168, Issue 6, Page 1075-11085.e9, Year 2017
Publish dateMar 9, 2017
AuthorsZachary Lee Johnson / Jue Chen /
PubMed AbstractThe multidrug resistance protein MRP1 is an ATP-binding cassette (ABC) transporter that confers resistance to many anticancer drugs and plays a role in the disposition and efficacy of several ...The multidrug resistance protein MRP1 is an ATP-binding cassette (ABC) transporter that confers resistance to many anticancer drugs and plays a role in the disposition and efficacy of several opiates, antidepressants, statins, and antibiotics. In addition, MRP1 regulates redox homeostasis, inflammation, and hormone secretion. Using electron cryomicroscopy, we determined the molecular structures of bovine MRP1 in two conformations: an apo form at 3.5 Å without any added substrate and a complex form at 3.3 Å with one of its physiological substrates, leukotriene C. These structures show that by forming a single bipartite binding site, MRP1 can recognize a spectrum of substrates with different chemical structures. We also observed large conformational changes induced by leukotriene C, explaining how substrate binding primes the transporter for ATP hydrolysis. Structural comparison of MRP1 and P-glycoprotein advances our understanding of the common and unique properties of these two important molecules in multidrug resistance to chemotherapy.
External linksCell / PubMed:28238471
MethodsEM (single particle)
Resolution3.34 - 3.49 Å
Structure data

8559

5uj9

EMDB-8559, PDB-5uj9:
Cryo-EM structure of bovine multidrug resistance protein 1 (MRP1)
Method: EM (single particle) / Resolution: 3.49 Å

8560

5uja

EMDB-8560, PDB-5uja:
Cryo-EM structure of bovine multidrug resistance protein 1 (MRP1) bound to leukotriene C4
Method: EM (single particle) / Resolution: 3.34 Å

Chemicals

ChemComp-LTX:
(5~{S},6~{R},7~{E},9~{E},11~{Z},14~{Z})-6-[(2~{R})-2-[[(4~{S})-4-azanyl-5-oxidanyl-5-oxidanylidene-pentanoyl]amino]-3-( / Leukotriene C4

Source
  • bos taurus (cattle)
KeywordsTRANSPORT PROTEIN / ABC transporter / multidrug resistance / PROTEIN TRANSPORT / leukotriene C4 / LTC4

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