| 1. |
|
|
| 2. |
|
|
| 3. |
- Razavi, Asghar M., et al.
(författare)
-
Molecular simulations and free-energy calculations suggest conformation-dependent anion binding to a cytoplasmic site as a mechanism for Na+/K+-ATPase ion selectivity
- 2017
-
Ingår i: Journal of Biological Chemistry. - : American Society for Biochemistry and Molecular Biology. - 0021-9258 .- 1083-351X. ; 292:30, s. 12412-12423
-
Tidskriftsartikel (refereegranskat)abstract
- Na+/K+-ATPase transports Na+ and K+ ions across the cell membrane via an ion-binding site becoming alternatively accessible to the intra- and extracellular milieu by conformational transitions that confer marked changes in ion-binding stoichiometry and selectivity. To probe the mechanism of these changes, we used molecular simulation and free-energy perturbation approaches to identify probable protonation states of Na+- and K+-coordinating residues in E1P and E2P conformations of Na+/K+-ATPase. Analysis of these simulations revealed a molecular mechanism responsible for the change in protonation state: the conformation-dependent binding of an anion (a chloride ion in our simulations) to a previously unrecognized cytoplasmic site in the loop between transmembrane helices 8 and 9, which influences the electrostatic potential of the crucial Na+-coordinating residue Asp(926). This mechanistic model is consistent with experimental observations and provides a molecular-level picture of how E1P to E2P enzyme conformational transitions are coupled to changes in ion-binding stoichiometry and selectivity.
|
|
| 4. |
- van Keulen, Siri Camee, et al.
(författare)
-
Does Proton Conduction in the Voltage-Gated H+ Channel hHv1 Involve Grotthuss-Like Hopping via Acidic Residues?
- 2017
-
Ingår i: Journal of Physical Chemistry B. - : American Chemical Society (ACS). - 1520-6106 .- 1520-5207. ; 15:121, s. 3340-3351
-
Tidskriftsartikel (refereegranskat)abstract
- Hv1 are ubiquitous highly selective voltage-gated proton channels involved in male fertility, immunology and the invasiveness of certain forms of breast cancer. The mechanism of proton extrusion in Hv1 is not yet understood while it constitutes the first step towards the design of high-affinity drugs aimed at this important pharmacological target. In this contribution, we explore the details of the mechanism via an integrative approach, using classical and QM/MM molecular dynamics simulations of a monomeric hHv1 model. We propose that protons localize in three binding sites along the channel lumen, formed by three pairs of conserved negatively charged residues lining the pore: D174/E153, D112/D185 and E119/D123. Local rearrangements, involving notably a dihedral transition of F150, a conserved phenylalanine lining the permeation pathway, appear to allow protons to hop from one acidic residue to the next through a bridging water molecule. These results constitute a first attempt at rationalizing hHv1 selectivity for H+ and the role of D112 in this process. They pave the way for further quantitative characterization of H+ transport in hHv1.
|
|
