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Göddeke H, Timachi MH, Hutter CAJ, et al. Atomistic Mechanism of Large-Scale Conformational Transition in a Heterodimeric ABC Exporter. J Am Chem Soc. 2018;140(13):4543-4551doi: 10.1021/jacs.7b12944.
Göddeke, H., Timachi, M. H., Hutter, C. A. J., Galazzo, L., Seeger, M. A., Karttunen, M., Bordignon, E., & Schäfer, L. V. (2018). Atomistic Mechanism of Large-Scale Conformational Transition in a Heterodimeric ABC Exporter. Journal of the American Chemical Society, 140(13), 4543-4551. https://doi.org/10.1021/jacs.7b12944
Göddeke, Hendrik, et al. "Atomistic Mechanism of Large-Scale Conformational Transition in a Heterodimeric ABC Exporter." Journal of the American Chemical Society vol. 140,13 (2018): 4543-4551. doi: https://doi.org/10.1021/jacs.7b12944
Göddeke H, Timachi MH, Hutter CAJ, Galazzo L, Seeger MA, Karttunen M, Bordignon E, Schäfer LV. Atomistic Mechanism of Large-Scale Conformational Transition in a Heterodimeric ABC Exporter. J Am Chem Soc. 2018 Apr 04;140(13):4543-4551. doi: 10.1021/jacs.7b12944. Epub 2018 Mar 26. PMID: 29547697.
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J Am Chem Soc. 2018 Apr 04;140(13):4543-4551. doi: 10.1021/jacs.7b12944. Epub 2018 Mar 26.

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

Journal of the American Chemical Society

Hendrik Göddeke, M Hadi Timachi, Cedric A J Hutter, Laura Galazzo, Markus A Seeger, Mikko Karttunen, Enrica Bordignon, Lars V Schäfer

Affiliations

  1. Theoretical Chemistry, Faculty of Chemistry and Biochemistry , Ruhr-University Bochum , 44780 Bochum , Germany.
  2. EPR Spectroscopy, Faculty of Chemistry and Biochemistry , Ruhr-University Bochum , 44780 Bochum , Germany.
  3. Institute of Medical Microbiology , University of Zürich , 8006 Zürich , Switzerland.
  4. Department of Chemistry and Department of Applied Mathematics , Western University , London , Ontario N6A 3K7 , Canada.

PMID: 29547697 DOI: 10.1021/jacs.7b12944

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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