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Mechanics and pharmacology of substrate selection and transport by eukaryotic ABC exporters

Nature Structural & Molecular Biology volume 26, pages 792–801 (2019)Cite this article

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Abstract

Much structural information has been amassed on ATP-binding cassette (ABC) transporters, including hundreds of structures of isolated domains and an increasing array of full-length transporters. The structures capture different steps in the transport cycle and have aided in the design and interpretation of computational simulations and biophysics experiments. These data provide a maturing, although still incomplete, elucidation of the protein dynamics and mechanisms of substrate selection and transit through the transporters. We present an updated view of the classical alternating-access mechanism as it applies to eukaryotic ABC transporters, focusing on type I exporters. Our model helps frame the progress in, and remaining questions about, transporter energetics, how substrates are selected and how ATP is consumed to perform work at the molecular scale. Many human ABC transporters are associated with disease; we highlight progress in understanding their pharmacology through the lens of structural biology and describe how this knowledge suggests approaches to pharmacologically targeting these transporters.

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Fig. 1: Structural similarities in ABCB, ABCC and ABCD exporters in contrast to ABCA and ABCG transporters.
Fig. 2: Experimentally identified substrate-interacting residues suggest binding-site diversity among ABC exporters.
Fig. 3: Consensus thermodynamic model for transport by ABC exporters.
Fig. 4: Structural insights into ABC-transporter pharmacology.

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Acknowledgements

We thank A. Murray and members of the laboratories of R.G. and A. Murray for insightful discussions. This work was funded in part by NIH grant R01GM120996 (to R.G.).

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  1. Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, USA

    Sriram Srikant & Rachelle Gaudet

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  1. Sriram Srikant
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  2. Rachelle Gaudet
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Correspondence to Rachelle Gaudet.

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Srikant, S., Gaudet, R. Mechanics and pharmacology of substrate selection and transport by eukaryotic ABC exporters. Nat Struct Mol Biol 26, 792–801 (2019). https://doi.org/10.1038/s41594-019-0280-4

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