Structural basis for the transport and regulation mechanism of the multidrug resistance-associated protein 2

Area of Science:

• Biochemistry
• Structural Biology
• Molecular Transport

Background:

• Multidrug resistance-associated protein 2 (MRP2) is an ATP-dependent transporter vital for liver homeostasis.
• MRP2 plays a significant role in cellular defense mechanisms and is implicated in chemotherapeutic resistance.

Purpose of the Study:

• To elucidate the structural mechanisms underlying human MRP2 function.
• To understand how MRP2 interacts with substrates and ATP to mediate transport.
• To provide insights into the structural basis of multidrug resistance associated with MRP2.

Main Methods:

• Cryogenic electron microscopy (cryo-EM) was employed to determine high-resolution structures of human MRP2.
• Structures were resolved in three distinct functional states: autoinhibited, substrate-bound pre-translocation, and ATP-bound post-translocation.
• Comparative structural analysis was performed on MRP2 bound to various substrates.

Main Results:

• The autoinhibited state features the cytosolic regulatory (R) domain blocking the substrate-binding site and forming part of the ATP-binding site.
• Substrate binding induces displacement of the R domain, initiating conformational changes required for transport.
• The R domain acts as a selectivity gauge, requiring sufficient substrate concentration to initiate transport.
• Structural analysis reveals how MRP2 recognizes diverse substrates, contributing to its role in multidrug resistance.

Conclusions:

• The R domain is critical for regulating MRP2 activity and substrate selectivity.
• Understanding MRP2's conformational states provides a mechanistic basis for its role in drug transport and resistance.
• These findings offer potential targets for modulating MRP2 activity in therapeutic contexts.