ABCG2 transports anticancer drugs via a closed-to-open switch

• Published in: Nature communications Vol. 11; no. 1; p. 2264
• Main Authors: Orlando, Benjamin J., Liao, Maofu
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.05.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 101/28; 13/31; 631/45/535/1258/1259; 631/67/1059/99; 82/83; ABC transporter; ABC transporters; Antibodies; Antineoplastic Agents - chemistry; Antineoplastic Agents - metabolism; Antineoplastic drugs; Antitumor agents; ATP Binding Cassette Transporter, Subfamily G, Member 2 - chemistry; ATP Binding Cassette Transporter, Subfamily G, Member 2 - metabolism; ATP Binding Cassette Transporter, Subfamily G, Member 2 - ultrastructure; Binding; Biological Transport; Cancer; Chemotherapy; Conformation; Disulfides - metabolism; HEK293 Cells; Humanities and Social Sciences; Humans; Imatinib; Imatinib Mesylate - metabolism; Ligands; Mitoxantrone - chemistry; Mitoxantrone - metabolism; Models, Biological; multidisciplinary; Protein Structure, Secondary; Science; Science (multidisciplinary); Transport
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-16155-2

ABCG2 is an ABC transporter that extrudes a variety of compounds from cells, and presents an obstacle in treating chemotherapy-resistant cancers. Despite recent structural insights, no anticancer drug bound to ABCG2 has been resolved, and the mechanisms of multidrug transport remain obscure. Such a gap of knowledge limits the development of novel compounds that block or evade this critical molecular pump. Here we present single-particle cryo-EM studies of ABCG2 in the apo state, and bound to the three structurally distinct chemotherapeutics. Without the binding of conformation-selective antibody fragments or inhibitors, the resting ABCG2 adopts a closed conformation. Our cryo-EM, biochemical, and functional analyses reveal the binding mode of three chemotherapeutic compounds, demonstrate how these molecules open the closed conformation of the transporter, and establish that imatinib is particularly effective in stabilizing the inward facing conformation of ABCG2. Together these studies reveal the previously unrecognized conformational cycle of ABCG2. ABCG2 is a human ABC transporter that actively extrudes a wide variety of compounds from cells but the mechanisms of multidrug transport remain obscure. Here authors present cryo-EM structures of ABCG2 in the apo state, and bound to the three structurally distinct chemotherapeutics and demonstrate how these molecules open the closed conformation of the transporter.