Structural basis of prostaglandin efflux by MRP4

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• Multidrug resistance protein 4 (MRP4) is an ATP-binding cassette transporter.
• MRP4 uniquely transports prostanoids, signaling molecules derived from unsaturated fatty acids.

Purpose of the Study:

• To elucidate the substrate selectivity of MRP4.
• To understand the transport mechanism of MRP4.

Main Methods:

• Cryogenic-electron microscopy (cryo-EM) was used to determine six structures of nanodisc-reconstituted MRP4.
• Structures were captured at various stages of the transport cycle, including substrate-bound states and a catalytically compromised mutant bound to ATP-Mg2+.

Main Results:

• Substrate-bound structures with PGE1, PGE2, and DHEA-S revealed a common binding site for diverse organic anions.
• An allosteric mechanism for substrate-induced enhancement of MRP4 ATPase activity was proposed.
• A catalytically compromised MRP4 mutant structure showed an outward-occluded conformation, suggesting an alternating-access transport mechanism.

Conclusions:

• The study provides structural insights into the endogenous function of MRP4.
• The findings establish a foundation for developing MRP4-targeted drugs.