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TitleStructural basis of prostaglandin efflux by MRP4.
Journal, issue, pagesNat Struct Mol Biol, Vol. 31, Issue 4, Page 621-632, Year 2024
Publish dateJan 12, 2024
AuthorsSergei Pourmal / Evan Green / Ruchika Bajaj / Ilan E Chemmama / Giselle M Knudsen / Meghna Gupta / Andrej Sali / Yifan Cheng / Charles S Craik / Deanna L Kroetz / Robert M Stroud /
PubMed AbstractMultidrug resistance protein 4 (MRP4) is a broadly expressed ATP-binding cassette transporter that is unique among the MRP subfamily for transporting prostanoids, a group of signaling molecules ...Multidrug resistance protein 4 (MRP4) is a broadly expressed ATP-binding cassette transporter that is unique among the MRP subfamily for transporting prostanoids, a group of signaling molecules derived from unsaturated fatty acids. To better understand the basis of the substrate selectivity of MRP4, we used cryogenic-electron microscopy to determine six structures of nanodisc-reconstituted MRP4 at various stages throughout its transport cycle. Substrate-bound structures of MRP4 in complex with PGE, PGE and the sulfonated-sterol DHEA-S reveal a common binding site that accommodates a diverse set of organic anions and suggest an allosteric mechanism for substrate-induced enhancement of MRP4 ATPase activity. Our structure of a catalytically compromised MRP4 mutant bound to ATP-Mg is outward-occluded, a conformation previously unobserved in the MRP subfamily and consistent with an alternating-access transport mechanism. Our study provides insights into the endogenous function of this versatile efflux transporter and establishes a basis for MRP4-targeted drug design.
External linksNat Struct Mol Biol / PubMed:38216659
MethodsEM (single particle)
Resolution2.7 - 3.5 Å
Structure data

EMDB-40821, PDB-8swn:
Bovine multidrug resistance protein 4 (MRP4) E1202Q mutant bound to ATP in MSP lipid nanodisc
Method: EM (single particle) / Resolution: 3.1 Å

EMDB-40826, PDB-8sx7:
Bovine multidrug resistance protein 4 (MRP4) bound to DHEA-S in MSP lipid nanodisc
Method: EM (single particle) / Resolution: 2.7 Å

EMDB-40827, PDB-8sx8:
Bovine multidrug resistance protein 4 (MRP4) bound to prostaglandin E1 in MSP lipid nanodisc
Method: EM (single particle) / Resolution: 3.5 Å

EMDB-40828, PDB-8sx9:
Inward-facing narrow conformation of bovine multidrug resistance protein 4 (MRP4) in MSP lipid nanodisc
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-40829, PDB-8sxa:
Inward-facing wide conformation of bovine multidrug resistance protein 4 (MRP4) in MSP lipid nanodisc
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-40830, PDB-8sxb:
Bovine multidrug resistance protein 4 (MRP4) bound to prostaglandin E2 in MSP lipid nanodisc
Method: EM (single particle) / Resolution: 2.9 Å

Chemicals

ChemComp-MG:
Unknown entry

ChemComp-PTY:
PHOSPHATIDYLETHANOLAMINE / phospholipid*YM / Phosphatidylethanolamine

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM / Adenosine triphosphate

ChemComp-ZWY:
17-oxoandrost-5-en-3beta-yl hydrogen sulfate

ChemComp-HOH:
WATER / Water

ChemComp-XPG:
7-[(1R,3R)-3-hydroxy-2-[(1E,3S)-3-hydroxyoct-1-en-1-yl]-5-oxocyclopentyl]heptanoic acid / medication*YM / Prostaglandin E1

ChemComp-P2E:
(Z)-7-[(1R,2R,3R)-3-hydroxy-2-[(E,3S)-3-hydroxyoct-1-enyl]-5-oxo-cyclopentyl]hept-5-enoic acid / medication*YM / Prostaglandin E2

Source
  • bos taurus (cattle)
  • bos indicus (zebu cattle)
KeywordsTRANSPORT PROTEIN / ABC transporter / multidrug resistance-associated protein / membrane protein

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