Abstract
Multidrug transporters of the ATP-binding cassette family export a wide variety of compounds across membranes in both prokaryotes and eukaryotes, using ATP hydrolysis as energy source. Several of these membrane proteins are of clinical importance. Although biochemical and structural studies have provided insights into the mechanism underlying substrate transport, many key questions subsist regarding the molecular and structural nature of this mechanism. In particular, the detailed conformational changes occurring during the catalytic cycle are still elusive. We explored the conformational changes occurring upon ATP/Mg(2+) binding using molecular dynamics simulations starting from the nucleotide-bound structure of SAV1866 embedded in an explicit lipid bilayer. The removal of nucleotide revealed a major rearrangement in the outer membrane leaflet portion of the transmembrane domain (TMD) resulting in the closure of the central cavity at the extracellular side. This closure is similar to that observed in the crystal nucleotide-free structures. The interface of the nucleotide-binding domain dimer (NDB) is significantly more hydrated in the nucleotide-free trajectory though it is not disrupted. This finding suggests that the TMD closure could occur as a first step preceding the dissociation of the dimer. The transmission pathway of the signal triggered by the removal of ATP/Mg(2+) mainly involves the conserved Q-loop and X-loop as well as TM6.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.