Structural highlights
FunctionPublication Abstract from PubMedMultidrug 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(1), PGE(2) 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(2+) 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. Structural basis of prostaglandin efflux by MRP4.,Pourmal S, Green E, Bajaj R, Chemmama IE, Knudsen GM, Gupta M, Sali A, Cheng Y, Craik CS, Kroetz DL, Stroud RM Nat Struct Mol Biol. 2024 Apr;31(4):621-632. doi: 10.1038/s41594-023-01176-4. , Epub 2024 Jan 12. PMID:38216659[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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