6vxi
From Proteopedia
Structure of ABCG2 bound to mitoxantrone
Structural highlights
Function[ABCG2_HUMAN] High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both from mitochondria to cytosol and from cytosol to extracellular space, and cellular export of hemin, and heme. Xenobiotic transporter that may play an important role in the exclusion of xenobiotics from the brain. Appears to play a major role in the multidrug resistance phenotype of several cancer cell lines. Implicated in the efflux of numerous drugs and xenobiotics: mitoxantrone, the photosensitizer pheophorbide, camptothecin, methotrexate, azidothymidine (AZT), and the anthracyclines daunorubicin and doxorubicin.[1] [2] [3] [4] Publication Abstract from PubMedABCG2 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 transports anticancer drugs via a closed-to-open switch.,Orlando BJ, Liao M Nat Commun. 2020 May 8;11(1):2264. doi: 10.1038/s41467-020-16155-2. PMID:32385283[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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