Structure of multidrug-resistance proteins of the ATP-binding cassette (ABC) superfamily

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Multidrug resistance (MDR) in tumors hinders cancer treatment by conferring resistance to diverse anticancer agents.
• Overexpression of ATP-binding cassette (ABC) proteins, such as P-glycoprotein and MRP1, is a primary cause of MDR.
• These ABC proteins function as plasma-membrane efflux pumps, actively removing chemotherapeutic drugs from cancer cells.

Purpose of the Study:

• To elucidate the molecular mechanisms underlying ATP-binding cassette (ABC) protein function in multidrug resistance.
• To investigate the role of nucleotide-binding domains (NBDs) and transmembrane domains (TMDs) in drug transport.
• To explore the proposed mechanism of NBD dimerization induced by ATP binding as a key step in substrate transport.

Main Methods:

• Analysis of the structural and functional properties of ATP-binding cassette (ABC) proteins.
• Investigation of the conserved structure of NBDs and their role in ATP binding/hydrolysis.
• Examination of the drug-binding sites within the transmembrane domains (TMDs).

Main Results:

• ABC proteins possess conserved NBDs responsible for ATP binding/hydrolysis and TMDs containing drug-binding sites.
• ATP binding induces NBD dimerization, proposed as a critical step for coupling ATP hydrolysis to substrate transport.
• In P-glycoprotein, ATP binding, rather than hydrolysis, appears to be the primary driver (power stroke) for drug transport, indicated by major conformational changes.

Conclusions:

• ATP-binding cassette (ABC) protein function is central to tumor multidrug resistance.
• NBD dimerization upon ATP binding is a key regulatory step in ABC transporter-mediated drug efflux.
• Understanding these mechanisms, particularly the role of ATP binding in P-glycoprotein, offers potential targets for overcoming chemotherapy resistance.