Conformational dynamics of the nucleotide binding domains and the power stroke of a heterodimeric ABC transporter

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Abstract

Multidrug ATP binding cassette (ABC) exporters are ubiquitous ABC transporters that extrude cytotoxic molecules across cell membranes. Despite recent progress in structure determination of these transporters, the conformational motion that transduces the energy of ATP hydrolysis to the work of substrate translocation remains undefined. Here, we have investigated the conformational cycle of BmrCD, a representative of the heterodimer family of ABC exporters that have an intrinsically impaired nucleotide binding site. We measured distances between pairs of spin labels monitoring the movement of the nucleotide binding (NBD) and transmembrane domains (TMD). The results expose previously unobserved structural intermediates of the NBDs arising from asymmetric configuration of catalytically inequivalent nucleotide binding sites. The two-state transition of the TMD, from an inward- to an outward-facing conformation, is driven exclusively by ATP hydrolysis. These findings provide direct evidence of divergence in the mechanism of ABC exporters.

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Smriti Mishra

Vanderbilt University, Nashville, United States

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The authors declare that no competing interests exist.
Brandy Verhalen

Vanderbilt University, Nashville, United States

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The authors declare that no competing interests exist.
Richard A Stein

Vanderbilt University, Nashville, United States

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The authors declare that no competing interests exist.
Po-Chao Wen

University of Illinois, Urbana, United States

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The authors declare that no competing interests exist.
Emad Tajkhorshid

University of Illinois, Urbana, United States

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The authors declare that no competing interests exist.
Hassane S Mchaourab

Vanderbilt University, Nashville, United States

For correspondence
hassane.mchaourab@vanderbilt.edu

Competing interests
The authors declare that no competing interests exist.

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