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

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

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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


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PubMed Central  Google Scholar  Download references 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.). AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, USA Sriram Srikant


 & Rachelle Gaudet Authors * Sriram Srikant View author publications You can also search for this author inPubMed Google Scholar * Rachelle Gaudet View author publications You can also


search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Rachelle Gaudet. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing interests.


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