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Atomistic Mechanism of Large-Scale Conformational Transition in a Heterodimeric ABC Exporter

Published inJournal of the American Chemical Society, vol. 140, no. 13, p. 4543-4551
Publication date2018-03-16
First online date2018-03-16
Abstract

ATP-binding cassette (ABC) transporters are ATP-driven molecular machines, in which ATP binding and hydrolysis in the nucleotide-binding domains (NBDs) is chemomechanically coupled to large-scale, alternating access conformational changes in the transmembrane domains (TMDs), ultimately leading to the translocation of substrates across biological membranes. The precise nature of the structural dynamics behind the large-scale conformational transition as well as the coupling of NBD and TMD motions is still unresolved. In this work, we combine all-atom molecular dynamics (MD) simulations with electron paramagnetic resonance (EPR) spectroscopy to unravel the atomic-level mechanism of the dynamic conformational transitions underlying the functional working cycle of the heterodimeric ABC exporter TM287/288. Extensive multimicrosecond simulations in an explicit membrane/water environment show how in response to ATP binding, TM287/288 undergoes spontaneous conformational transitions from the inward-facing (IF) state via an occluded (Occ) intermediate to an outward-facing (OF) state. The latter two states have thus far not been characterized at atomic level. ATP-induced tightening of the NBD dimer involves closing and reorientation of the two NBD monomers concomitant with a closure of the intracellular TMD gate, which leads to the occluded state. Subsequently, opening at the extracellular TMD gate yields the OF conformer. The obtained mechanism imposes NBD-TMD coupling via a tight orchestration of conformational transitions, between both the two domains and also within the TMDs, ensuring that the cytoplasmic and periplasmic gate regions are never open simultaneously.

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Citation (ISO format)
GÖDDEKE, Hendrik et al. Atomistic Mechanism of Large-Scale Conformational Transition in a Heterodimeric ABC Exporter. In: Journal of the American Chemical Society, 2018, vol. 140, n° 13, p. 4543–4551. doi: 10.1021/jacs.7b12944
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ISSN of the journal0002-7863
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