The first intracellular loop is essential for the catalytic cycle of the human ABCG2 multidrug resistance transporter

FEBS Letters

article

Narakorn Khunweeraphong¹  Karl Kuchler¹ 

[1] Max Perutz Labs Vienna, Center for Medical Biochemistry, Campus Vienna Biocenter, Medical University of Vienna;St. Anna Children’s Cancer Research Institute-CCRI

关键词: ABCG2;    anticancer drug resistance;    ATP-binding cassette transporter;    catalytic cycle;    transmission interface;    transport mechanism;   

DOI  :  10.1002/1873-3468.13994

来源: John Wiley & Sons Ltd.

【 摘 要 】

The human multidrug transporter ABCG2 is required for physiological detoxification and mediates anticancer drug resistance. Here, we identify pivotal residues in the first intracellular loop (ICL1), constituting an intrinsic part of the transmission interface. The architecture includes a triple helical bundle formed by the hot spot helix of the nucleotide-binding domain, the elbow helix, and ICL1. We show here that the highly conserved ICL1 residues G462, Y463, and Y464 are essential for the proper cross talk of the closed nucleotide-binding domain dimer with the transmembrane domains. Hence, ICL1 acts as a molecular spring, triggering the conformational switch of ABCG2 before substrate extrusion. These data suggest that the ABCG2 transmission interface may offer therapeutic options for the treatment of drug-resistant malignancies.

【 授权许可】

Unknown